PRKCD (protein kinase C, delta)

Written2008-02Yadira Malavez, M Elba Gonzalez-Mejia, Andrea I Doseff
201 Heart, Lung Research Institute, Dept. Molecular Genetics. Div. Pulmonary, Critical Care. The Ohio State University, 473 West 12th Ave., Columbus, OH 43210, USA

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1. Identity

General Information
Other aliasAI385711
LocusID (NCBI) 5580
Atlas_Id 42901
Location 3p21.1  [Link to chromosome band 3p21]
Location_base_pair Starts at 53161207 and ends at 53192717 bp from pter ( according to hg19-Feb_2009)  [Mapping PRKCD.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
CACNA1D (3p21.1) / PRKCD (3p21.1)LAMTOR1 (11q13.4) / PRKCD (3p21.1)NECTIN1 (11q23.3) / PRKCD (3p21.1)
PRKCD (3p21.1) / PRKCD (3p21.1)PRKCD (3p21.1) / TBC1D8 (2q11.2)PRKCD (3p21.1) / TFIP11 (22q12.1)
RDH5 (12q13.2) / PRKCD (3p21.1)


Description The gene encompasses 36 kb of DNA and contains 18 exons.
Transcription 2.2 kb mRNA.

3. Protein

Note The protein kinase C (PKC) is a family of serine/threonine kinases that plays key roles in cell proliferation and apoptosis (Berridge 1984; Nishizuka 1992). The mammalian PKC family consists of 11 different isoforms named PKCα, PKCβI, PKCβII, PKCγ, PKCδ, PKCε, PKCζ, PKCη, PKCθ, PKCι and PKCλ. Based on their requirements the PKC family is divided in 3 subfamilies: the conventional (cPKC) are regulated by diacylglycerol (DAG) and Ca2+. They are composed by the α, βI, βII, γ isoforms; the novel PKCs (nPKC) composed by the δ, ε, η, θ isoforms are regulated only by DAG and the atypical PKC (aPKC), composed by the ζ and ι/λ isoforms are activated by phorbol esther and they are independent of DAG and Ca2+(Mellor and Parker 1998; Gschwendt 1999; Basu 2003).
  Figure 1. Structural domains and phosphorylation sites on PKCδ.
Description - Structure
PKCδ, a member of the novel PKC group, is a 78 kDa protein composed of a regulatory and a catalytic domain. The N-terminal regulatory domain contains an auto-inhibitory region named the pseudosubstrate and four conserved domains, the C1 and C2 in the regulatory region and the C3 and C4 motifs in the catalytic region. PKCδ contains also five variable regions (V). The variable region 3 (V3), called the hinge region, separates the catalytic and regulatory domains (Cho 2001; Basu 2003) (Figure 1).
The C1 motif contains DAG/PMA (Phorbol 12-myristate 13-acetate) binding sequences that allow the interaction to a hydrophilic cleft located at a hydrophobic surface of this domain. The binding to the hydrophobic cleft forms a contiguous hydrophobic surface that promotes PKC binding to membranes. PKCδ has a C2-like region located at the N terminal domain. It has the same core residues of the C2 domain, but it lacks the essential calcium coordinating acidic residues that allows classical PKCs to bind Ca2+ (Pappa, Murray-Rust et al. 1998). The C3 and C4 are required for ATP/substrate binding and catalytic activity of the enzyme. The pseudosubstrate domain, located between the C1 and C2 motifs, maintains PKCδ in an inactive conformation by blocking the access to the substrate binding pocket. The proteolytic activation of PKCδ generates a 40 kDa fragment that can translocate to the mitochondria and/or nucleus (Hurley and Misra 2000; Cho 2001; Steinberg 2004) (Table 1).
Table 1. Important domains of PKCδ.
DomainAmino acid sequenceFunction
PKCδ translocation inhibitorS8FNSYELGSL17;Prevents translocation to cell membrane (Inagaki, Chen et al. 2003)
PKCδ translocation activatorM74RAAEDPM81;Binding of cell membrane (Jaken and Parker 2000)
Pseudosubstrate domainP140TMNRRGAIKQAKIHY155IKN158Prevents PKCδ activation by blocking the substrate binding pocket (Dempsey, Newton et al. 2000)
Caspase cleavage siteY311QGFEKKTAVSGNDIPDNNGTY332GKISequence cleaved by caspase-3 (Blake, Garcia-Paramio et al. 1999)
ATP binding sequenceG361KGSFGKVLLAELKGK376Binding site for ATP. Promotes catalytic activity (Hurley and Misra 2000)
Activation loopRAST505FCGTPDY512IAPEILQGLKY523Contains important phosphorylation sites necessary for the catalytic activation (Thr505, Thr512, Thr523) (Rybin, Sabri et al. 2003)
Nuclear localization signal (NLS)K611RKVEPPFKPKVKSPSDY628STargets PKCδ to the nucleus (DeVries, Neville et al. 2002)
Turn motifS643Auto-phosphorylation site important for PKCδ maturation (Rybin, Sabri et al. 2003)
Hydrophobic motifS662Facilitate PKCδ down-regulation by releasing it from the cell membrane (Feng, Becker et al. 2000; Rybin, Sabri et al. 2003)

- Isotypes
So far eight PKCδ isotypes, generated by alternative splicing, have been identified in different species. PKCδ isotypes show different characteristics. PKCδI is the only isotype expressed in all species and is a target of caspase-3 (Sakurai, Onishi et al. 2001). In contrast, the PKCδII isotype is present in mouse and is insensitive to caspase-3 cleavage. PKCδIII is expressed in rats and shows weak translocation to the cell membrane upon stimulation by phorbol esther (Ueyama, Ren et al. 2000). PKCδIV, PKCδV, PKCδVI, and PKCδVII are expressed exclusively in mouse testis and they lack the V1 and C2-like domains. PKCδIV and PKCδV are expressed in spermatids, during mice's sperm maturation, while PKCδVI and PKCδVII are expressed in spermatigonia and spermatocytes (Kawaguchi, Niino et al. 2006). PKCδVIII is expressed in humans upon retinoic acid treatment. This isotype is resistant to caspase-3 cleavage and its expression rescues NT2 cells from etoposide-induced apoptosis. This suggest an antiapoptotic role for the PKCδVIII isotype in NT2 cells (Jiang, Apostolatos et al. 2008).
  Figure 2. Phosphorylation sites and evolutionary conservation. Conserved phosphorylation sites important for PKCδ activity. (Accession numbers: Homo sapiens: NP-997704; Canis lupus familiaris: NP-001008716; Mus musculus: AAH51416; Rattus norvegicus: AAH76505; Oryctolagus cuniculus: AAW34270)
Expression - Phosphorylation sites
There are several phosphorylable sites that depending on the stimuli and/or cell type have a different contribution on the activation of PKCδ. Three phosphorylation sites are conserved among all PKC isotypes: Thr505 (activation loop), Ser643 (turn motif), and Ser662 (hydrophobic motif) (Steinberg 2004). In PKCδ, these three sites were shown to be substantially phosphorylated in vivo (Konishi, Yamauchi et al. 2001). However, unlike the other PKCs, mutations of Thr505 to Ala in PKCδ doesn't affect its kinase activity, but seems to regulate PKCδ stability (Stempka, Girod et al. 1997). The phosphorylation of Ser643 and Ser662 seems to be important for PKCδ's catalytic maturation. Ser643 is auto-phosphorylated, however the phosphorylation of Ser662 has been shown to be regulated by PKCζ and a pathway involving the mammalian target of rapamycin (mTOR) (Ziegler, Parekh et al. 1999). PKCδ has eight Tyr residues (located at position 52, 155, 187, 311, 332, 512, 523, and 565), that can be phosphorylated by tyrosine kinases. These phosphorylation sites are conserved among species, but only Tyr512 is conserved in other members of the PKC family. Phosphorylation at Tyr155 has been involved in the inhibitory effect of PKCδ on cell proliferation whereas Tyr64 and Thr187 are the mayor sites for PMA-dependent phosphorylation in etoposide-induced apoptosis (Szallasi Z et al. 1995, Sun X et al. 2000). Phosphorylation at Tyr311, Tyr332 and Tyr512 at the hinge and activation regions induce PKCδ activation and differential subcellular distribution onto the membranes (Konishi, Tanaka et al. 1997; Blake, Garcia-Paramio et al. 1999) (Table 1, Figure 3). In contrast, the phosphorylation of Tyr155 and Tyr187 are important for the anti-apoptotic effect of PKCδ. Mutation of this sites to phosphor-mimicking mutants results in an increase in cell proliferation in response to PMA (Kronfeld, Kazimirsky et al. 2000). The association of PKCδ and different tyrosine kinases results in different phosphorylation patterns and possibly differential activation of downstream targets in response to specific stimulus. Tyrosine kinases like Src (Sarcoma), Fyn, Lyn (v-yes-1 Yamaguchi sarcoma viral related oncogene homolog), PDK1 (Phosphoinoisitide dependent kinase 1), PYK2 (Protein tyrosine kinase 2) have been shown to phosphorylate PKCδ (Gschwendt, Kielbassa et al. 1994; Li, Mischak et al. 1994; Szallasi, Denning et al. 1995; Song, Swann et al. 1998; Yuan, Utsugisawa et al. 1998; Balendran, Hare et al. 2000; Sun, Wu et al. 2000; Wrenn 2001).
See figure 2.
- Activation
PKC family members exist in an immature inactive conformation that requires post-translational modifications to achieve catalytic maturity before activation by DAG/PMA. cPKC, nPKC and aPKC are subject to phosphorylation of the activation loop and this event acts as a priming step that allows the catalytic maturation of PKC (Dutil, Toker et al. 1998). The catalytic maturation of PKCδ involves the auto-phosphorylation of Ser643 and the phosphorylation of Thr505 and Ser662. It has been proposed that the phosphorylation of Ser643 is the first step for PKCδ maturation, since Ser662 is subject of dephosphorylation in the absence of Thr505 phosphorylation (Parekh, Ziegler et al. 1999). Phosphorylation of Ser643 can be mediated by PKCζ, in 293 cells or by the mammalian target of rapamicin (mTOR) (Le Good, Ziegler et al. 1998; Parekh, Ziegler et al. 1999; Ziegler, Parekh et al. 1999; Wood, Kelly et al. 2007) (Figure 2). PKCδ also interacts with the mTOR homolog in Saccharomyces cerevisiae, FRAP and its necessary for the FRAP-dependent phosphorylation of 4e-BP1 (4e-binding protein 1) (Kumar, Pandey et al. 2000).
PDK1 phosphorylates PKCδ in Thr505 stabilizing PKCδ's structure promoting the alignment of these residues with the catalytic pocket (PKCδ immature inactive). In contrast with other members of the PKC family, the phosphorylation of this residue seems not to be necessary for the catalytic activity of PKCδ, since PKCδ exhibits full enzymatic activity in the absence of the Thr505 phosphorylation, in vitro (Stempka, Schnolzer et al. 1999). It is possible that the negative charge provided by the phosphate required for the catalytic activation of PKCδ is provided by the Glu500. Glu500, located in the activation loop, seems to play an important role on PKCδ activity since the mutation of this aminoacid to Val exhibits a reduction of 70% in auto-phosphorylation and substrate phosphorylation (Stempka, Schnolzer et al. 1999). After the phosphorylation of Thr505, autophosphorylion of Ser662 occurs and this event allows the catalytic maturation of PKCδ. However, even after the auto-phosphorylation of this residue, PKCδ remains in an inactive conformation due to the interaction of the pseudosubstrate domain with the substrate-binding region of the catalytic site.
Upon stimulation by DAG or PMA, PKCδ is also auto-phosphorylated at the conserved residues: S299, S302 and S304, located in the V3 region. The phosphorylated PKCδ translocates to the plasma and nuclear membrane (Durgan, Michael et al. 2007). Phosphorylation of Ser299 has been proposed to be a marker for PKCδ catalytic activation, since it only occurs after its translocation to the plasma and nuclear membrane (Durgan, Michael et al. 2007). PKCδ can bind membranes through its C1/C2 domains. The binding induces a conformational change that allows the release of the pseudosubstrate domain from the substrate-binding site. This event allows PKCδ phosphorylation of membrane substrates (Steinberg 2004). Tyrosine kinases like: Src, Lyn, have been shown to phosphorylate residues on the T-loop region of the C4 domain in response to different apoptotic inducers and non-apoptotic stimuli (Denning, Dlugosz et al. 1996; Shanmugam, Krett et al. 1998; Kikkawa, Matsuzaki et al. 2002). The phosphorylation of PKCδ in specific tyrosine residues regulates PKCδ localization and activity depending on the cell type and stimuli (Song, Swann et al. 1998; Yuan, Utsugisawa et al. 1998; Konishi, Yamauchi et al. 2001; Blass, Kronfeld et al. 2002). PKCδ is proteolytically cleaved by caspase-3 at the hinge region, separating the regulatory domain from the catalytic domain (Figure 2). The cleavage creates a 40 kDa catalytically active fragment (CF). The proteolytic activation of PKCδ can be modulated by tyrosine phosphorylation. Overexpression of Y52F, Y155F and Y565F mutants in glial cells enhances the apoptotic response to etoposide induced apoptosis; however the overexpression of Y64F and Y187F reduces caspase-3-dependent PKCδ activation and reduced etoposide-induced apoptosis (Blass, Kronfeld et al. 2002).
Notably, unlike other PKC-family members, PKCδ can act as a lipid-independent enzyme and can be entirely activated without translocation to the cell membrane (Steinberg 2004). PKCδ can localize to the mitochondria after activation by PMA in U937 cells causing the release of cytochrome C and activation of caspase-3 (Majumder, Pandey et al. 2000). The catalytic fragment of PKCδ translocates to the nucleus utilizing its NLS (nuclear localization signal) and triggers apoptosis (Emoto, Manome et al. 1995; Ghayur, Hugunin et al. 1996). Consistent with this, the expression of PKCδ caspase-3-uncleavable-mutant reduces its nuclear accumulation. Furthermore, mutations within the NLS of CF reduce PKCδ nuclear accumulation and apoptosis in salivary acinar cells (Figure 2) (DeVries, Neville et al. 2002). However, cell death induction of LNCap cells treated with phorbol esthers, CHO cells treated with H2O2 and HaCaT cells UV irradiated doesn't induce caspase-3-deppendent cleavage of PKCδ (Fujii, Garcia-Bermejo et al. 2000; Fukunaga, Oka et al. 2001; Konishi, Yamauchi et al. 2001).
After activation by 12-O-tetradecanoylphorbol-13-acetate (TPA), PKCδ is ubiquitinated and targeted to the proteasome for degradation. Treatment with the proteasome inhibitors, MG101 and MG132, prevents TPA-induced depletion of PKCδ in rat fibroblasts (Lu, Liu et al. 1998).
See figure 3
- Substrates
Several proteins with diverse biological activity have been shown to be substrates of PKCδ (Yoshida 2007). PKCδ modulates translational elongation factors, such as eEF-1α (eukaryotic elongation factor 1-α) which upon treatment with TPA is activated by phosphorylation at Thr431 (Kielbassa, Muller et al. 1995). PKCδ interacts and regulates the activity of mTOR (mammalian target of rapamycin), an important regulator of the 4E-BPs, required to control translation modulating the translation initiation factor eIF4E (Kumar, Pandey et al. 2000). In addition, PKCδ regulates the function of several transcription factors such as Sp1, NF-κB, p300, Stat1, Stat3, among others (Novotny-Diermayr, Zhang et al. 2002; Yuan, Soh et al. 2002; Liu, Yang et al. 2006; Gorelik, Fang et al. 2007; Kim, Lim et al. 2007; Kwon, Yao et al. 2007). The role of each transcription factor will be further explained in the transcriptional regulation section.
During mast cell activation, PKCδ phosphorylates the IgE (immunoglobulin E) receptor causing its endocytosis (Germano, Gomez et al. 1994). In addition, PKCδ maintains homeostasis by phosphorylating the calcium efflux regulator PMCA (plasma membrane calcium ATPase) regulating Ca2+ levels in the skin (Garcia and Strehler 1999; Ahn, Jeong et al. 2007). PKCδ phosphorylates GIRK channels to normalize K+ levels after membrane depolarization 2 (Breitwieser 2005; Brown, Thomas et al. 2005; Xie, John et al. 2007). Moreover, during hypertrophy of vascular smooth muscle cells, PKCδ mediates the transactivation of the EGF receptor and activates ERK1, ERK2, PI3K and ATF-1 signalling pathways, leading to the up-regulation of NOX1 (Fan, Katsuyama et al. 2005).
PKCδ has an important role as a modulator of cell death in different cell types and the interaction of this protein kinase with multiple of its substrates induces apoptosis. Exposure of keratinocytes to UV light induces the PKCδ-dependent phosphorylation of Mcl-1 (the myeloid cell leukemia protein 1) causing the release of cytochrome c and subsequently activation of apoptosis (D'Costa and Denning 2005; Sitailo, Tibudan et al. 2006). Phosphorylation of the checkpoint protein Rad9 by PKCδ also positively regulates apoptosis by promoting the binding of Rad9 to Bcl-2 (Yoshida, Wang et al. 2003). Most recently caspase-3, a key mediator of apoptosis, was shown to associate and be phosphorylated by PKCδ in human primary monocytes. The phosphorylation of caspase-3 promotes its apoptotic activity in vivo and in vitro (Voss, Kim et al. 2005). Moreover, silencing of PKCδ reduced etoposide-induced apoptosis and consistently overexpression of a PKCδ-cat increased caspase-3-dependent apoptosis (Voss, Kim et al. 2005). PKCδ phosphorylates also the tumor suppressor p53 at Ser46, inducing cell death (Yoshida, Liu et al. 2006).
Oxidative stress induces the formation of a PKCδ-p52Shc-p66Shc complex allowing PKCδ phosphorylation of p52 at Ser29, p66 at Ser138. The phosphorylation of p66Shc at Ser138 is crucial for H2O2 induced ERK activation (Hu, Kang et al. 2007). Furthermore, PKCδ interacts, phosphorylates Abl tyrosine kinase, in response to H2O2 treatment. As a consequence of this interaction, PKCδ is also phosphorylated by Abl showing an active interaction between the two kinases in response to oxidative stress (Sun, Wu et al. 2000). In addition, the release of nitric oxide in the cells causes the activation of PKCδ by tyrosine nitration, leading to the phosphorylation p53 at Ser15, which in turn increases the stability of p53 by destabilizing MDM2 (murine double minute), leading to cell death (Lee, Kim et al. 2006). Recently, it was shown that the interaction of the heat shock protein 25 (Hsp25, the mouse homolog of the human Hsp27) through the direct binding with the PKCδ V5 catalytic region inhibits apoptosis (Lee, Lee et al. 2005). Taken together, the diversity of PKCδ substrates demonstrates the central role of this kinase in diverse biological processes.
See figure 4
Sequence (Fasta Format): NP 997704
PKCδ-Phosphorylable Consensus Sequence
S/TXXR/K (X represents any amino acid) (Yoshida, Wang et al. 2003).
  Figure 3. Model of PKCδ activation. Sequential activation and subcellular localization of PKCδ are illustrated in the model
Localisation The localization of PKCδ seems to play an important role in determining its activity. PMA-induced activation of PKCδ causes its translocation from the cytoplasm to the plasma membrane. This event is followed by a slower nuclear membrane translocation in hamster ovary cells (Wang, Bhattacharyya et al. 1999). Induction of apoptosis by TNF and Fas mediates the release of ceramide, causing PKCδ translocation from the plasma membrane to the cytosol in leukemia cells (Sawai, Okazaki et al. 1997). The released ceramide accumulates at the Golgi causing the translocation of PKCδ to this cellular compartment. Ceramide induces the phosphorylation of PKCδ at Tyr311 and Tyr332 via Src kinase (Sarcoma), inducing its activation. Treatment with TPA causes PKCδ translocation from the Golgi to the plasma membrane suggesting that PKCδ moves continuously from the Golgi complex to the cytoplasm (Kajimoto, Ohmori et al. 2001). Moreover, in glioma cells, PKCδ was found to induce cell death when targeted to the mitochondria, cytoplasm, and nucleus. However, in the case of glioma cells, localization of PKCδ to the endoplasmic reticulum was suggested to protect glioma cells from etoposide and TNF-ligand induced cell death (Gomel, Xiang et al. 2007). It has been suggested recently that nuclear localization of PKCδ in response to Fas ligand, etoposide, ionizing radiation and growth factor deprivation is required for its ability to induce apoptosis (Yuan, Utsugisawa et al. 1998; Scheel-Toellner, Pilling et al. 1999; Blass, Kronfeld et al. 2002). Transfection of the PKCδ catalytic fragment (CF) in parotid salivary acinar cells induces nuclear localization of PKCδ and apoptosis. Mutations in the NLS motif of CF were show to inhibit cell death, demonstrating the importance of PKCδ's CF nuclear localization in apoptosis. However, the translocation of full-length PKCδ to the nucleus has also been suggested (DeVries, Neville et al. 2002).
  Figure 4. Model of PKCδ and its substrates.
Function - Apoptosis
PKCδ has been emerging as an important regulator of apoptosis. This apoptotic function is achieved by its interaction and phosphorylation of several proteins that are involved in the cell death (Basu 2003). For example, PKCδ associates and phosphorylates caspase-3 promoting the apoptotic activity of the cysteine caspase during etoposide-induced apoptosis and also in spontaneous apoptosis of monocytes (Voss, Kim et al. 2005). Apoptosis induced by diverse agents including: TNF-α or Fas ligation, etoposide, mitomycin, cytosine arabinoside, etoposide, UV, and ionizing radiation induces the cleavage of PKCδ, freeing the catalytically from the regulatory domain (Emoto, Manome et al. 1995; Datta, Banach et al. 1996; Ghayur, Hugunin et al. 1996; Park, Park et al. 2000; Fukunaga, Oka et al. 2001; Blass, Kronfeld et al. 2002). The cleavage of PKCδ occurs at a specific amino-acid site (see Table 1) and is mediated by caspase-3. It was suggested that the PKCδ catalytic fragment may serve to amplify downstream events in the apoptotic pathway, for example by allowing the relocalization of the catalytic domain into the nucleus where is able then to phosphorylate an additional repertoire of substrates (Brodie and Blumberg 2003). Consistent with this hypothesis, overexpression of the catalytic fragment in the absence of an apoptotic stimulus was sufficient to induce apoptosis in a variety of cell types (Leverrier, Vallentin et al. 2002). Hence, it has been suggested that PKCδ operates in a feedback loop to regulate apoptosis. PKCδ participates in the early events of apoptosis by modulating the activation of caspase-3 and later, downstream of the caspase activation, by phosphorylating proteins of diverse biological function that in turn regulate the execution of cell death (Basu 2003).
Consistent with a central role of PKCδ in apoptosis, PKCδ-/- mice were found to be protected against γ-irradiation induced apoptosis (Humphries, Limesand et al. 2006). Moreover, glioma cells treated with etoposide in the presence of rottlerin, a PKCδ inhibitor, showed lack of PKCδ activation and absence of the caspase-3-dependent PKCδ cleaved catalytic domain, suggesting an essential team-work of PKCδ and capase-3 in the induction of apoptosis (Blass, Kronfeld et al. 2002). The apoptotic activity of PKCδ is controlled, at least in part, by a member of the heat shock family. The heat shock protein 25 (Hsp25, the mouse homolog of the human Hsp27) was shown to inhibit apoptosis through the direct binding PKCδ's V5 catalytic region. Consistent with this mechanisms, Hsp25 inhibited PKCδ kinase activity and membrane translocation reducing cell death in mouse fibroblasts (Lee, Lee et al. 2005) (Figure 4).
- Homeostasis and membrane exitability
PKCδ regulates membrane excitability by modulating different ion channels and pumps such as the calcium efflux regulator PMCA (plasma membrane calcium ATPase) (Crotty, Cai et al. 2006; Ahn, Jeong et al. 2007). In the skin, if the permeability barrier is disrupted by physical or mechanical damage, there is an increase on trans-epidermal water loss, followed by a decrease of the extracellular Ca2+ levels (Garcia and Strehler 1999). The decrease in Ca2+ levels causes the opening of calcium channels allowing calcium influx to restore basal levels of Ca2+. Accumulation of Ca2+ in the cell causes the activation of phospholipase C (PLCγ). The activated phospholipase cleaves phosphatidylinositol 4,5-biphosphate (PI(4,5)P2) generating DAG and inositol 1,4,5-triphosphate which in turn activate PKCδ (Figure 4) (Berridge 1984). Thus, PKCδ is fundamental to maintain Ca2+ levels and the homeostatic balance in the skin.
In muscle cells, PKCδ plays an important role restoring K+ homeostasis after membrane depolarization of the action potential. Membrane depolarization caused by an excitatory stimulus activates Na+ pumps; this causes an inward movement of Na+ ions. The entrance of Na+ ions causes a decrease of membrane negative charge and a change to a positive inner membrane potential. The inner positive electrical gradient favors the activation of the G protein-activated Inwardly Rectifying K+ channels (GIRK channels) to open and release K+, this allows the transmission of a second impulse. Activation of the G-coupled protein causes the generation of PI(4,5)P2 and DAG through PLCγ activation (Berridge 1984). After PKCδ is recruited to the membrane, is able to phosphorylate the GIRK channels leading to the alteration of the channel's conformation and/or interactions with Gβγ-subunits, preventing a channel activation by PI(4,5)P 2. This allows the cell to maintain the homeostasis by normalizing potassium basal levels (Breitwieser 2005; Brown, Thomas et al. 2005; Xie, John et al. 2007).
- Transcriptional regulation
Multiple transcription factors are phosphorylated by PKCδ (Kim, Seo et al. 2006; Liu, Yang et al. 2006; Kim, Choi et al. 2007; Kim, Lim et al. 2007). In this context, phosphorylation of the Sp1 transcription factor, promoted cyclin D3 expression in cells treated with the histone deacetylase apicidin (Kim, Lim et al. 2007). Moreover, the expression of NF-κB was modulated by apicidin, through the inhibition of Sp1. PI3K and PKC are required for the NFκB activation by apicidin. In addition NF-κB plays an important role as a modulator determining cell fate in response to HDAC inhibitors (Kim, Seo et al. 2006; Liu, Yang et al. 2006). Also, it has been observed that RelA / NF-κB upregulate PKCδ expression, in UV treated cells. PKCδ is necessary and sufficient to mediate JNK activation by RelA, in response to UV treatment promoting apoptosis in mouse fibroblasts (Liu, Yang et al. 2006) (Figure 4). In addition, PKCδ can modulate DNA methylation through induced-phosphorylation of transcription factors, and through the modulation of the ERK signal pathway (Yuan, Soh et al. 2002; Gorelik, Fang et al. 2007). PKCδ also phosphorylates the acetyl transferase p300 at Ser89 inhibiting its activity in vitro and in vivo. This event inhibits p300 histone acetyl transferase (HAT) activity causing a reduction in the nucleosome histone acetylation and reduction of gene expression on HeLa cells (Yuan, Soh et al. 2002) (Figure 4). Moreover, members of the Stat transcription factor family are regulated by PKCδ. PKCδ phosphorylates Stat1 (signal transducer transactivator-1) at Ser727, allowing the transcription of the CIITA (class II transactivator) promoter promoting the activity of the MHC class II receptor (Kwon, Yao et al. 2007). PKCδ also phosphorylates and associates with Stat-3 enhancing the interaction between Stat3 and IL-6 receptor subunit glycoprotein (gp) 130, the initial step for Stat3 activation (Novotny-Diermayr, Zhang et al. 2002).
- Redox-sensitive kinase
PKCδ functions as a redox-sensitive kinase in various cell types (Sun, Wu et al. 2000; Kanthasamy, Kitazawa et al. 2003). Exposure to reactive oxygen species (ROS) induces the release of DAG, activation and membrane translocation (Cummings, Parinandi et al. 2002). ROS can induce the activation of the NF-κB signaling pathway through the activation of the IκB kinases (IKKs), in a PKCδ signal pathway dependent manner (Yamaguchi, Miki et al. 2007). Thus, PKCδ may regulate the role of NF-κB as a redox-sensitive factor (Figure 4).
- Immunological response
The regulation of the antigen presentation is a key to generate an effective immune response. CD1 family members are antigenic peptides presented by MHC class I or class II molecules (Jackman, Moody et al. 1999; Brutkiewicz, Lin et al. 2003). Inhibition of PKCδ by rottlerin results in a substantial reduction in CD1d-mediated antigen presentation and alters the intracellular localization of CD1d to the lipid membrane. Also, PKCδ can modulate the expression levels of the trans-activator MHC class II, CD28, and CD24 , mediating a negative feedback signals in lymphocytes though the phosphorylation of MHC class I and II (Brutkiewicz, Lin et al. 2003). PKCδ activation also promotes the mobilization of the MHC class II receptors to the cell surface. Inhibition of PKCδ activation by rottlerin prevents dendritic cell activation of T lymphoctes (Majewski, Bose et al. 2007). In addition, PKCδ can regulate the expression of MHC class II receptor controlling the expression of the class II transactivator (CIITA). The expression of CIITA is required for MHC class II expression (Reith, LeibundGut-Landmann et al. 2005). Upon inflammation macrophages release IFNγ causing the activation of PKCδ. Once PKCδ is activated, induces the phosphorylation of Stat-1 at Ser727 allowing it to interact with the HATs, CBP/p300, promoting acetylation of the CIITA promoter. The PKCδ-dependent transcription of CIITA allows MHC class II expression in murine macrophages (Kwon, Yao et al. 2007) (Figure 4).

4. Implicated in

Entity Breast Cancer
Disease The role of PKCδ in breast cancer has been suggested by numerous investigators (Signorelli and Ghidoni 2005). A decrease in PKCδ expression upon acquisition of a metastatic phenotype has been observed in MCF-7 breast cancer tumor cells (Jackson, Zheng et al. 2005). Estrogen has been shown to up-regulate the expression of the PKCδ isoform (Cutler, Maizels et al. 1994). Anti-estrogen treatment of MCF-7 cells reduced PKCδ protein and mRNA levels in MCF-7 cells (Shanmugam, Krett et al. 1999). Anti-estrogenic drugs such as tamoxifen (Ueyama, Ren et al.) are used currently as treatment for the management of hormone-responsive breast tumors. The development of resistance to this drug presents a challenge for the treatment of breast cancer. Overexpression of PKCδ leads to Tam resistance in MCF-7 cells while the treatment with rottlerin and siRNA inhibits estrogen and Tam-induced growth in anti-estrogen resistant cells (Nabha, Glaros et al. 2005).
Entity Systemic Lupus Erythematosus (SLE)
Disease Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by alteration of the cellular and humoral immune response, leading to pathological autoantibody production. While the cause of lupus remains unknown (Tsokos, Wong et al. 2000; Yang, Wang et al. 2007), dysfunctional monocytes/macrophages and T lymphocytes have been reported in SLE patients (Steinbach, Henke et al. 2000). Clinical studies showed decreased levels of PKCδ in monocytes from SLE patients. Hence, monocytes prolonged survival and accumulation of macrophages, have been suggested as contributing factors to the development of the disease (Biro, Griger et al. 2004). PKCδ plays an essential role regulating monocyte life span by directly contributing to the activation of caspase-3 (Voss, Kim et al. 2005). Moreover, PKCδ-/- animals have increased lymphocyte numbers and develop SLE (Leitges, Mayr et al. 2001; Miyamoto, Nakayama et al. 2002). Defects on T cell-ERK pathway signaling causes a lupus-like disease in mice and a decrease in DNA methyltransferase expression, leading to epigenetic changes. Interestingly, T cells treated with hydrazine, a lupus inducing drug, showed inhibition of PMA-induced activation of PKCδ and halted its translocation to the membrane suggesting a link with the role for PKCδ in lupus (Gorelik, Fang et al. 2007).
Entity Parkinson's disease (PD)
Disease Parkinson's disease (PD) is an idiopathic neurodegenerative disorder characterized by profound loss of dopaminergic neurons in the nigrostriatal tract (Simon, Mayeux et al. 2000). As consequence of PD neurites lost followed by neuronal cell apoptosis have been documented. PKCδ has been described as an oxidative stress-sensitive kinase and a key mediator of apoptosis in neurons of PD patients (Clarke 2007). Correlation between the exposure to vehicle and industrial emissions, such as methylcyclopentadienyl manganese tricarbonyl (MMT) and the development of PD has been suggested (Finkelstein and Jerrett 2007). Prolonged exposure to MMT showed pronounced accumulation of manganese in the brain resulting in depletion of dopamine in striatum increasing the risk of PD (Gianutsos and Murray 1982; Zheng, Kim et al. 2000). The direct exposure of MMT in PC12 cells (granular neurons) resulted in a profound activation of caspase-3 and PKCδ. The activation of caspase-3 followed by the cleavage of PKCδ, generates the active catalytic fragment of PKCδ, and mediates neuronal cell death in PD (Anantharam, Kitazawa et al. 2002).
Entity Diabetes mellitus type 2 (Diabetes mellitus type II, non insulin-dependent diabetes (NIDDM))
Disease NIDDM is the most common form of diabetes primarily characterized by insulin resistance, relative insulin deficiency, and hyperglycemia. One of the secondary pathologies in NIDDM is retinopathy, characterized by pericytes and retinal neurons apoptosis, followed by the gradual lost of sight. Neurons and glial retinal cells present high levels of the small heat shock protein αB-crystallin (αBC), an important regulator against apoptotic stress. The αBC acts as a stress-response molecular chaperone. Up-regulation of αBC has been associated with a glial cell reaction to neuronal damage in the eye, and is part of a defense response to apoptotic stress in NIDDM (Lorenzi and Gerhardinger 2001; Alge, Priglinger et al. 2002; Cheung, Fung et al. 2005). Phosphorylation of αBC at Ser59 is necessary and sufficient for its anti-apoptotic function. PKCδ associates with αBC in the retina, suggesting that PKCδ is closely involved in αBC phosphorylation (Kim, Choi et al. 2007).
Entity Listeria monocytogenes
Disease Listeria monocytogenes (Scheel-Toellner, Pilling et al.) is a Gram-positive, facultative intracellular bacterium that infects humans through the ingestion of contaminated food. The infection of immunocompromised individuals can result in meningitis and septicemia (Drevets, Leenen et al. 2004). LM evades the immune system by escaping from macrophage vacuoles into the cytoplasm, avoiding macrophage phagocytosis (Tilney and Portnoy 1989). After infection, activated macrophages produce reactive oxygen intermediates, reactive nitrogen intermediates and phosphatidylinositol specific phospholipase C ( PI-PLC ) (Yoshida 2007). PLC allows the generation of DAG and increases the intracellular calcium levels. Once DAG is generated it can activate PKCδ allowing its translocation to the cell membranes (Wadsworth and Goldfine 2002; Myers, Tsang et al. 2003). Upon infection, macrophages also activate NF-16, a transcription factor downstream of IFN-γ and TNF. IF-IL6 required for macrophages to kill bacteria (Tanaka, Akira et al. 1995). PKCδ-deficient mice showed high susceptibility to LM infection despite the high mRNA expression of IF-IL6. PKCδ has been shown to regulate NF-IL6 activity through direct phosphorylation and its activity is critical for macrophage bacterial-killing activity during LM infection (Schwegmann, Guler et al. 2007).
Entity Atherosclerosis
Disease Atherosclerosis is a chronic inflammatory response in arterial walls due to the deposition of lipoproteins that causes the formation of multiple plaques within the arteries. The initial lesions in atherogenesis involve proliferation of the intima smooth muscle cells (SMCs), followed by the formation of plaque (Ross 1993). It has been reported that PKCδ inhibits growth, induces differentiation, and promotes apoptosis in vascular SMCs (Fukumoto, Nishizawa et al. 1997). SMC proliferation/accumulation in the intima of the vessel wall is a key event in the development of atherosclerosis (Ross 1993; Von der Thusen, Van Berkel et al. 2001). PKCδ has a critical role in the development of atherosclerosis since PKCδ knockout mice develop severe atherosclerosis in the vein's grafts, compared to the PKCδ+/+ mice. Caspase-3 activation was also affected in PKCδ -/- mice demonstrating the importance of PKCδ's activity activating cell death, an important event for the prevention of vein graft disease (Leitges, Mayr et al. 2001).

5. Bibliography

Role of PKC-d as a signal mediator in epidermal barrier homeostasis.
Ahn BK, Jeong SK, Lee SH.
Arch Dermatol Res 2007; 299: 53-57.
PMID 17464524
Retinal pigment epithelium is protected against apoptosis by aB-crystallin.
Alge CS, Priglinger SG, Neubauer AS, Kampik A, Zillig M, Bloemendal H, Welge-Lussen U.
Invest Ophthalmol Vis Sci 2002; 43: 3575-3582.
PMID 12407170
Caspase-3-dependent proteolytic cleavage of protein kinase Cd is essential for oxidative stress-mediated dopaminergic cell death after exposure to methylcyclopentadienyl manganese tricarbonyl.
Anantharam V, Kitazawa M, Wagner J, Kaul S, Kanthasamy AG.
J Neurosci 2002; 22: 1738-1751.
PMID 11880503
Further evidence that 3-phosphoinositide-dependent protein kinase-1 (PDK1) is required for the stability and phosphorylation of protein kinase C (PKC) isoforms.
Balendran A, Hare GR, Kieloch A, Williams MR, Alessi DR.
FEBS Lett 2000; 484: 217-223.
PMID 11078882
Involvement of protein kinase C-d in DNA damage-induced apoptosis.
Basu A.
J Cell Mol Med 2003; 7: 341-350.
PMID 14754503
Inositol trisphosphate and diacylglycerol as second messengers.
Berridge MJ.
Biochem J 1984; 220: 345-360.
PMID 6146314
Abnormal cell-specific expressions of certain protein kinase C isoenzymes in peripheral mononuclear cells of patients with systemic lupus erythematosus: effect of corticosteroid application.
Biro T, Griger Z, Kiss E, Papp H, Aleksza M, Kovacs I, Zeher M, Bodolay E, Csepany T, Szucs K, Gergely P, Kovacs L, Szegedi G, Sipka S.
Scand J Immunol 2004; 60: 421-428.
PMID 15379867
Src promotes PKCd degradation.
Blake RA, Garcia-Paramio P, Parker PJ, Courtneidge SA.
Cell Growth Differ 1999; 10: 231-241.
PMID 10319993
Tyrosine phosphorylation of protein kinase C d is essential for its apoptotic effect in response to etoposide.
Blass M, Kronfeld I, Kazimirsky G, Blumberg PM, Brodie C.
Mol Cell Biol 2002; 22: 182-195.
PMID 11739733
GIRK channels: hierarchy of control. Focus on PKC-d sensitizes Kir3.1/3.2 channels to changes in membrane phospholipid levels after M3 receptor activation in HEK-293 cells.
Breitwieser GE.
Am J Physiol Cell Physiol 2005; 289: C509-511.
PMID 16100388
Regulation of cell apoptosis by protein kinase c d.
Brodie C, Blumberg PM.
Apoptosis 2003; 8: 19-27.
PMID 12510148
PKC-d sensitizes Kir3.1/3.2 channels to changes in membrane phospholipid levels after M3 receptor activation in HEK-293 cells.
Brown SG, Thomas A, Dekker LV, Tinker A, Leaney JL.
Am J Physiol Cell Physiol 2005; 289: C543-556.
PMID 15857907
CD1d-mediated antigen presentation to natural killer T (NKT) cells.
Brutkiewicz RR, Lin Y, Cho S, Hwang YK, Sriram V, Roberts TJ.
Crit Rev Immunol 2003; 23: 403-419.
PMID 15030309
Aldose reductase deficiency prevents diabetes-induced blood-retinal barrier breakdown, apoptosis, and glial reactivation in the retina of db/db mice.
Cheung AKH, Fung MKL, Lo ACY, Lam TTL, So KF, Chung SSM, Chung SK.
Diabetes 2005; 54: 3119-3125.
PMID 16249434
Membrane targeting by C1 and C2 domains.
Cho W.
J Biol Chem 2001; 276: 32407-32410.
PMID 11432875
Parkinson's disease.
Clarke CE.
BMJ 2007; 335: 441-445.
PMID 17762036
Diacylglycerol kinase d regulates protein kinase C and epidermal growth factor receptor signaling.
Crotty T, Cai J, Sakane F, Taketomi A, Prescott SM, Topham MK.
Proc Natl Acad Sci U S A 2006; 103: 15485-15490.
PMID 17021016
Phospholipase D/phosphatidic acid signal transduction: role and physiological significance in lung.
Cummings R, Parinandi N, Wang L, Usatyuk P, Natarajan V.
Mol Cell Biochem 2002; 234-235: 99-109.
PMID 12162465
Deta protein kinase-C in the rat ovary: estrogen regulation and localization.
Cutler RE Jr, Maizels ET, Hunzicker-Dunn M.
Endocrinology 1994; 135: 1669-1678.
PMID 7925131
A caspase-resistant mutant of PKCd protects keratinocytes from UV-induced apoptosis.
D'Costa AM, Denning MF.
Cell Death Differ 2005; 12: 224-232.
PMID 15618968
Activation of the CPP32 protease in apoptosis induced by 1-ß-D-arabinofuranosylcytosine and other DNA-damaging agents.
Datta R, Banach D, Kojima H, Talanian RV, Alnemri ES, Wong WW, Kufe DW.
Blood 1996; 88: 1936-1943.
PMID 7890750
Nuclear import of PKCd is required for apoptosis: identification of a novel nuclear import sequence.
DeVries TA, Neville MC, Reyland ME.
Embo J 2002; 21: 6050-6060.
PMID 12426377
Protein kinase C isozymes and the regulation of diverse cell responses.
Dempsey EC, Newton AC, Mochly-Rosen D, Fields AP, Reyland ME, Insel PA, Messing RO.
Am J Physiol Lung Cell Mol Physiol 2000; 279: L429-438.
PMID 10956616
Activation of the epidermal growth factor receptor signal transduction pathway stimulates tyrosine phosphorylation of protein kinase C d.
Denning MF, Dlugosz AA, Threadgill DW, Magnuson T, Yuspa SH.
J Biol Chem 1996; 271: 5325-5331.
PMID 8621384
Invasion of the central nervous system by intracellular bacteria.
Drevets DA, Leenen PJ, Greenfield RA.
Clin Microbiol Rev 2004; 17: 323-347.
PMID 15084504
Novel phosphorylation site markers of protein kinase C d activation.
Durgan J, Michael N, Totty N, Parker PJ.
FEBS Lett 2007; 581: 3377-3381.
PMID 17603046
Regulation of conventional protein kinase C isozymes by phosphoinositide-dependent kinase 1 (PDK-1).
Dutil EM, Toker A, Newton AC.
Curr Biol 1998; 8: 1366-1375.
PMID 9889098
Proteolytic activation of protein kinase C d by an ICE-like protease in apoptotic cells.
Emoto Y, Manome Y, Meinhardt G, Kisaki H, Kharbanda S, Robertson M, Ghayur T, Wong WW, Kamen R, Weichselbaum R, et al.
Embo J 1995; 14: 6148-6156.
PMID 7890750
PKCd mediates up-regulation of NOX1, a catalytic subunit of NADPH oxidase, via transactivation of the EGF receptor: possible involvement of PKCd in vascular hypertrophy.
Fan CY, Katsuyama M, Yabe-Nishimura C.
Biochem J 2005; 390: 761-767.
PMID 15913451
Regulation of receptor-mediated protein kinase C membrane trafficking by autophosphorylation.
Feng X, Becker KP, Stribling SD, Peters KG, Hannun YA.
J Biol Chem 2000; 275: 17024-17034.
PMID 10828076
A study of the relationships between Parkinson's disease and markers of traffic-derived and environmental manganese air pollution in two Canadian cities.
Finkelstein MM, Jerrett M.
Environ Res 2007; 104: 420-432.
PMID 17445792
Involvement of protein kinase C d (PKCd) in phorbol ester-induced apoptosis in LNCaP prostate cancer cells. Lack of proteolytic cleavage of PKCd.
Fujii T, Garcia-Bermejo ML, Bernabo JL, Caamano J, Ohba M, Kuroki T, Li L, Yuspa SH, Kazanietz MG.
J Biol Chem 2000; 275: 7574-7582.
PMID 10713064
Protein kinase C d inhibits the proliferation of vascular smooth muscle cells by suppressing G1 cyclin expression.
Fukumoto S, Nishizawa Y, Hosoi M, Koyama H, Yamakawa K, Ohno S, Morii H.
J Biol Chem 1997; 272: 13816-13822.
PMID 9153238
UV-induced tyrosine phosphorylation of PKC d and promotion of apoptosis in the HaCaT cell line.
Fukunaga M, Oka M, Ichihashi M, Yamamoto T, Matsuzaki H, Kikkawa U.
Biochem Biophys Res Commun 2001; 289: 573-579.
PMID 11716513
Plasma membrane calcium ATPases as critical regulators of calcium homeostasis during neuronal cell function.
Garcia ML, Strehler EE.
Front Biosci 1999; 4: D869-882.
PMID 10577388
Phosphorylation of the gamma chain of the high affinity receptor for immunoglobulin E by receptor-associated protein kinase C-d.
Germano P, Gomez J, Kazanietz MG, Blumberg PM, Rivera J.
J Biol Chem 1994; 269: 23102-23107.
PMID 8083212
Proteolytic activation of protein kinase C d by an ICE/CED 3-like protease induces characteristics of apoptosis.
Ghayur T, Hugunin M, Talanian RV, Ratnofsky S, Quinlan C, Emoto Y, Pandey P, Datta R, Huang Y, Kharbanda S, Allen H, Kamen R, Wong W, Kufe D.
J Exp Med 1996; 184: 2399-2404.
PMID 8976194
Alterations in brain dopamine and GABA following inorganic or organic manganese administration.
Gianutsos G, Murray MT.
Neurotoxicology 1982; 3: 75-81.
PMID 6891761
The localization of protein kinase C d in different subcellular sites affects its proapoptotic and antiapoptotic functions and the activation of distinct downstream signaling pathways.
Gomel R, Xiang C, Finniss S, Lee HK, Lu W, Okhrimenko H, Brodie C.
Mol Cancer Res 2007; 5: 627-639.
PMID 17579121
Impaired T cell protein kinase C d activation decreases ERK pathway signaling in idiopathic and hydralazine-induced lupus.
Gorelik G, Fang JY, Wu A, Sawalha AH, Richardson B.
J Immunol 2007; 179: 5553-5563.
PMID 17911642
Tyrosine phosphorylation and stimulation of protein kinase C d from porcine spleen by src in vitro. Dependence on the activated state of protein kinase C d.
Gschwendt M, Kielbassa K, Kittstein W, Marks F.
FEBS Lett 1994; 347: 85-89.
PMID 7516899
Protein kinase C d.
Gschwendt M.
Eur J Biochem 1999; 259: 555-564.
PMID 10092837
PKC d phosphorylates p52ShcA at Ser29 to regulate ERK activation in response to H2O2.
Hu Y, Kang C, Philp RJ, Li B.
Cell Signal 2007; 19: 410-418.
PMID 16963224
Suppression of apoptosis in the protein kinase Cd null mouse in vivo.
Humphries MJ, Limesand KH, Schneider JC, Nakayama KI, Anderson SM, Reyland ME.
J Biol Chem 2006; 281: 9728-9737.
PMID 16452485
Signaling and subcellular targeting by membrane-binding domains.
Hurley JH, Misra S.
Annu Rev Biophys Biomol Struct 2000; 29: 49-79.
PMID 10940243
Inhibition of d-protein kinase C protects against reperfusion injury of the ischemic heart in vivo.
Inagaki K, Chen L, Ikeno F, Lee FH, Imahashi K, Bouley DM, Rezaee M, Yock PG, Murphy E, Mochly-Rosen D.
Circulation 2003; 108: 2304-2307.
PMID 14597593
Mechanisms of lipid antigen presentation by CD1.
Jackman RM, Moody DB, Porcelli SA.
Crit Rev Immunol 1999; 19: 49-63.
PMID 9987600
Suppression of cell migration by protein kinase Cd.
Jackson D, Zheng Y, Lyo D, Shen Y, Nakayama K, Nakayama KI, Humphries MJ, Reyland ME, Foster DA.
Oncogene 2005; 24: 3067-3072.
PMID 15735725
Protein kinase C binding partners.
Jaken S, Parker PJ.
Bioessays 2000; 22: 245-254.
PMID 10684584
Identification of a novel antiapoptotic human Protein Kinase C d isoform, PKCdVIII in NT2 cells.
Jiang K, Apostolatos AH, Ghansah T, Watson JE, Vickers T, Cooper DR, Epling-Burnette PK, Patel NA.
Biochemistry 2008; 47: 787-797.
PMID 18092819
Subtype-specific translocation of the d subtype of protein kinase C and its activation by tyrosine phosphorylation induced by ceramide in HeLa cells.
Kajimoto T, Ohmori S, Shirai Y, Sakai N, Saito N.
Mol Cell Biol 2001; 21: 1769-1783.
PMID 11238914
Role of proteolytic activation of protein kinase Cd in oxidative stress-induced apoptosis.
Kanthasamy AG, Kitazawa M, Kanthasamy A, Anantharam V.
Antioxid Redox Signal 2003; 5: 609-620.
PMID 14580317
New PKCd family members, PKCdIV, dV, dVI, and dVII are specifically expressed in mouse testis.
Kawaguchi T, Niino Y, Ohtaki H, Kikuyama S, Shioda S.
FEBS Lett 2006; 580: 2458-2464.
PMID 16638571
Protein kinase C d-specific phosphorylation of the elongation factor eEF-a and an eEF-1 a peptide at threonine 431.
Kielbassa K, Muller HJ, Meyer HE, Marks F, Gschwendt M.
J Biol Chem 1995; 270: 6156-6162.
PMID 7890750
Protein kinase C d (PKCd): activation mechanisms and functions.
Kikkawa U, Matsuzaki H, Yamamoto T.
J Biochem (Tokyo) 2002; 132: 831-839.
PMID 12473183
Protein kinase C d regulates anti-apoptotic aB-crystallin in the retina of type 2 diabetes.
Kim YH, Choi MY, Kim YS, Han JM, Lee JH, Park CH, Kang SS, Choi WS, Cho GJ.
Neurobiol Dis 2007; 28:293-303.
PMID 17904375
Expression of cyclin D3 through Sp1 sites by histone deacetylase inhibitors is mediated with protein kinase C-d (PKCd) signal pathway.
Kim YH, Lim JH, Lee TJ, Park JW, Kwon TK.
J Cell Biochem 2007; 101: 987-995.
PMID 17407153
Involvement of HDAC1 and the PI3K/PKC signaling pathways in NFKB activation by the HDAC inhibitor apicidin.
Kim YK, Seo DW, Kang DW, Lee HY, Han JW, Kim SN.
Biochem Biophys Res Commun 2006; 347: 1088-1093.
PMID 16870149
Activation of protein kinase C by tyrosine phosphorylation in response to H2O2.
Konishi H, Tanaka M, Takemura Y, Matsuzaki H, Ono Y, Kikkawa U, Nishizuka Y.
Proc Natl Acad Sci U S A 1997; 94: 11233-11237.
PMID 9326592
Phosphorylation sites of protein kinase C d in H2O2-treated cells and its activation by tyrosine kinase in vitro.
Konishi H, Yamauchi E, Taniguchi H, Yamamoto T, Matsuzaki H, Takemura Y, Ohmae K, Kikkawa U, Nishizuka Y.
Proc Natl Acad Sci U S A 2001; 98: 6587-6592.
PMID 11381116
Phosphorylation of protein kinase Cd on distinct tyrosine residues regulates specific cellular functions.
Kronfeld I, Kazimirsky G, Lorenzo PS, Garfield SH, Blumberg PM, Brodie C.
J Biol Chem 2000; 275: 35491-35498.
PMID 10945993
Functional interaction between RAFT1/FRAP/mTOR and protein kinase cd in the regulation of cap-dependent initiation of translation.
Kumar V, Pandey P, Sabatini D, Kumar M, Majumder PK, Bharti A, Carmichael G, Kufe D, Kharbanda S.
Embo J 2000; 19: 1087-1097.
PMID 10698949
Role of PKCd in IFN-gamma-inducible CIITA gene expression.
Kwon MJ, Yao Y, Walter MJ, Holtzman MJ, Chang CH.
Mol Immunol 2007; 44: 2841-2849.
PMID 17346795
Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1.
Le Good JA, Ziegler WH, Parekh DB, Alessi DR, Cohen P, Parker PJ.
Science 1998; 281: 2042-2045.
PMID 9748166
Regulation of p53 by activated protein kinase C-d during nitric oxide-induced dopaminergic cell death.
Lee SJ, Kim DC, Choi BH, Ha H, Kim KT.
J Biol Chem 2006; 281: 2215-2224.
PMID 16314418
HSP25 inhibits protein kinase Cd-mediated cell death through direct interaction.
Lee Y-J, Lee D-H, Cho C-K, Bae S, Jhon G-J, Lee S-J, Soh J-W, Lee Y-S.
J Biol Chem 2005; 280: 18108-18119.
PMID 15731106
HSP25 inhibits radiation-induced apoptosis through reduction of PKCd-mediated ROS production.
Lee YJ, Lee DH, Cho CK, Chung HY, Bae S, Jhon GJ, Soh JW, Jeoung DI, Lee SJ, Lee YS.
Oncogene 2005; 24: 3715-3725.
PMID 15806174
Exacerbated vein graft arteriosclerosis in protein kinase Cd-null mice.
Leitges M, Mayr M, Braun U, Mayr U, Li C, Pfister G, Ghaffari-Tabrizi N, Baier G, Hu Y, Xu Q.
J. Clin. Invest. 2001; 108: 1505-1512.
PMID 11714742
Positive feedback of protein kinase C proteolytic activation during apoptosis.
Leverrier S, Vallentin A, Joubert D.
Biochem. J. 2002; 368: 905-913.
PMID 12238950
Tyrosine phosphorylation of protein kinase C-d in response to its activation.
Li W, Mischak H, Yu JC, Wang LM, Mushinski JF, Heidaran MA, Pierce JH.
J Biol Chem 1994; 269: 2349-2352.
PMID 7507923
NF-kappaB is required for UV-induced JNK activation via induction of PKCd.
Liu J, Yang D, Minemoto Y, Leitges M, Rosner MR, Lin A.
Mol Cell 2006; 21: 467-480.
PMID 16483929
Early cellular and molecular changes induced by diabetes in the retina.
Lorenzi M, Gerhardinger C.
Diabetologia 2001; 44: 791-804.
PMID 11508263
Activation of protein kinase C triggers its ubiquitination and degradation.
Lu Z, Liu D, Hornia A, Devonish W, Pagano M, Foster DA.
Mol. Cell. Biol. 1998; 18: 839-845.
PMID 9447980
Protein kinase C d stimulates antigen presentation by Class II MHC in murine dendritic cells.
Majewski M, Bose TO, Sille FC, Pollington AM, Fiebiger E, Boes M.
Int Immunol 2007; 19: 719-732.
PMID 17446207
Mitochondrial translocation of protein kinase C d in phorbol ester-induced cytochrome c release and apoptosis.
Majumder PK, Pandey P, Sun X, Cheng K, Datta R, Saxena S, Kharbanda S, Kufe D.
J Biol Chem 2000; 275: 21793-21796.
PMID 10818086
The extended protein kinase C superfamily.
Mellor H, Parker PJ.
Biochem J 1998; 332 (Pt 2): 281-292.
PMID 9601053
Increased proliferation of B cells and auto-immunity in mice lacking protein kinase Cd.
Miyamoto A, Nakayama K, Imaki H, Hirose S, Jiang Y, Abe M, Tsukiyama T, Nagahama H, Ohno S, Hatakeyama S, Nakayama KI.
Nature 2002; 416: 865-869.
PMID 11976687
Localized reactive oxygen and nitrogen intermediates inhibit escape of Listeria monocytogenes from vacuoles in activated macrophages.
Myers JT, Tsang AW, Swanson JA.
J Immunol 2003; 171: 5447-5453.
PMID 14607950
Upregulation of PKCd contributes to antiestrogen resistance in mammary tumor cells.
Nabha SM, Glaros S, Hong M, Lykkesfeldt AE, Schiff R, Osborne K, Reddy KB.
Oncogene 2005; 24: 3166-3176.
PMID 15735693
Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C.
Nishizuka Y.
Science 1992; 258: 607-614.
PMID 1411571
Protein kinase C d associates with the interleukin-6 receptor subunit glycoprotein (gp) 130 via Stat3 and enhances Stat3-gp130 interaction.
Novotny-Diermayr V, Zhang T, Gu L, Cao X.
J Biol Chem 2002; 277: 49134-49142.
PMID 12361954
Crystal structure of the C2 domain from protein kinase C-d.
Pappa H, Murray-Rust J, Dekker LV, Parker PJ, McDonald NQ.
Structure 1998; 6: 885-894.
PMID 9687370
Mammalian TOR controls one of two kinase pathways acting upon nPKCd and nPKCe.
Parekh D, Ziegler W, Yonezawa K, Hara K, Parker PJ.
J Biol Chem 1999; 274: 34758-34764.
PMID 10574945
Mitomycin C induces apoptosis in a caspases-dependent and Fas/CD95-independent manner in human gastric adenocarcinoma cells.
Park IC, Park MJ, Hwang CS, Rhee CH, Whang DY, Jang JJ, Choe TB, Hong SI, Lee SH.
Cancer Lett 2000; 158: 125-132.
PMID 10960761
Regulation of MHC class II gene expression by the class II transactivator.
Reith W, LeibundGut-Landmann S, Waldburger JM.
Nat Rev Immunol 2005; 5: 793-806.
PMID 16200082
The pathogenesis of atherosclerosis: a perspective for the 1990s.
Ross R.
Nature 1993; 362: 801-809.
PMID 8479518
Cross-regulation of novel protein kinase C (PKC) isoform function in cardiomyocytes. Role of PKCe in activation loop phosphorylations and PKCd in hydrophobic motif phosphorylations.
Rybin VO, Sabri A, Short J, Braz JC, Molkentin JD, Steinberg SF.
J Biol Chem 2003; 278: 14555-14564.
PMID 12566450
Novel protein kinase C d isoform insensitive to caspase-3.
Sakurai Y, Onishi Y, Tanimoto Y, Kizaki H.
Biol Pharm Bull 2001; 24: 973-977.
PMID 11558579
Ceramide-induced translocation of protein kinase C-d and -e to the cytosol. Implications in apoptosis.
Sawai H, Okazaki T, Takeda Y, Tashima M, Sawada H, Okuma M, Kishi S, Umehara H, Domae N.
J. Biol. Chem. 1997; 272: 2452-2458.
PMID 8999958
Inhibition of T cell apoptosis by IFN-beta rapidly reverses nuclear translocation of protein kinase C-PKCd
Scheel-Toellner D, Pilling D, Akbar AN, Hardie D, Lombardi G, Salmon M, Lord JM.
Eur J Immunol 1999; 29: 2603-2612.
PMID 10458775
Protein kinase Cd is essential for optimal macrophage-mediated phagosomal containment of Listeria monocytogenes.
Schwegmann A, Guler R, Cutler AJ, Arendse B, Horsnell WGC, Flemming A, Kottmann AH, Ryan G, Hide W, Leitges M, Seoighe C, Brombacher F.
Proc Natl Acad Sci U S A 2007; 104: 16251-16256.
PMID 17913887
Regulation of protein kinase C d by estrogen in the MCF-7 human breast cancer cell line.
Shanmugam M, Krett NL, Maizels ET, Cutler RE Jr, Peters CA, Smith LM, O'Brien ML, Park-Sarge OK, Rosen ST, Hunzicker-Dunn M.
Mol Cell Endocrinol 1999; 148: 109-118.
PMID 10221776
Breast cancer and sphingolipid signalling.
Signorelli P, Ghidoni R.
J Dairy Res 2005; 72: 5-13.
PMID 16180715
Mitochondrial DNA mutations in complex I and tRNA genes in Parkinson's disease.
Simon DK, Mayeux R, Marder K, Kowall NW, Beal MF, Johns DR.
Neurology 2000; 54: 703-709.
PMID 10680807
The protein kinase C d catalytic fragment targets MCL-1 for degradation to trigger apoptosis.
Sitailo LA, Tibudan SS, Denning MF.
J Biol Chem 2006; 281:29703-29710.
PMID 16901898
Tyrosine phosphorylation-dependent and -independent associations of protein kinase PKCd with Src family kinases in the RBL-2H3 mast cell line: regulation of Src family kinase activity by protein kinase C-d.
Song JS, Swann PG, Szallasi Z, Blank U, Blumberg PM, Rivera J.
Oncogene 1998; 16: 3357-3368.
PMID 9692543
Monocytes from systemic lupus erythematous patients are severely altered in phenotype and lineage flexibility.
Steinbach F, Henke F, Krause B, Thiele B, Burmester GR, Hiepe F.
Ann Rheum Dis 2000; 59: 283-288.
PMID 10733475
Distinctive activation mechanisms and functions for protein kinase Cd.
Steinberg SF.
Biochem J 2004; 384: 449-459.
PMID 15491280
Phosphorylation of protein kinase C d (PKCd) at threonine 505 is not a prerequisite for enzymatic activity. Expression of rat PKCd and an alanine 505 mutant in bacteria in a functional form.
Stempka L, Girod A, Muller HJ, Rincke G, Marks F, Gschwendt M, Bossemeyer D.
J Biol Chem 1997; 272: 6805-6811.
PMID 9045715
Requirements of protein kinase cd for catalytic function. Role of glutamic acid 500 and autophosphorylation on serine 643.
Stempka L, Schnolzer M, Radke S, Rincke G, Marks F, Gschwendt M.
J Biol Chem 1999; 274: 8886-8892.
PMID 10085132
Interaction between protein kinase C d and the c-Abl tyrosine kinase in the cellular response to oxidative stress.
Sun X, Wu F, Datta R, Kharbanda S, Kufe D.
J Biol Chem 2000; 275: 7470-7473.
PMID 10713049
Development of a rapid approach to identification of tyrosine phosphorylation sites: application to PKCd phosphorylated upon activation of the high affinity receptor for IgE in rat basophilic leukemia cells.
Szallasi Z, Denning MF, Chang EY, Rivera J, Yuspa SH, Lehel C, Olah Z, Anderson WB, Blumberg PM.
Biochem Biophys Res Commun 1995; 214: 888-894.
PMID 7575560
Targeted disruption of the NF-IL6 gene discloses its essential role in bacteria killing and tumor cytotoxicity by macrophages.
Tanaka T, Akira S, Yoshida K, Umemoto M, Yoneda Y, Shirafuji N, Fujiwara H, Suematsu S, Yoshida N, Kishimoto T.
Cell 1995; 80: 353-361.
PMID 7890750
Actin filaments and the growth, movement, and spread of the intracellular bacterial parasite, Listeria monocytogenes.
Tilney LG, Portnoy DA.
J Cell Biol 1989; 109: 1597-1608.
PMID 2507553
Immune cell signaling in lupus.
Tsokos GC, Wong HK, Enyedy EJ, Nambiar MP.
Curr Opin Rheumatol 2000; 12: 355-363.
PMID 10990169
cDNA cloning of an alternative splicing variant of protein kinase C d (PKCdIII), a new truncated form of PKCd, in rats.
Ueyama T, Ren Y, Ohmori S, Sakai K, Tamaki N, Saito N.
Biochem Biophys Res Commun 2000; 269: 557-563.
PMID 10708593
Induction of rapid atherogenesis by perivascular carotid collar placement in apolipoprotein E-deficient and low-density lipoprotein receptor-deficient mice.
Von der Thusen JH, Van Berkel TJC, Biessen EAL.
Circulation 2001; 103: 1164-1170.
PMID 11222482
Regulation of monocyte apoptosis by the protein kinase Cd-dependent phosphorylation of caspase-3.
Voss OH, Kim S, Wewers MD, Doseff AI.
J Biol Chem 2005; 280: 17371-17379.
PMID 15716280
Mobilization of protein kinase C in macrophages induced by Listeria monocytogenes affects its internalization and escape from the phagosome.
Wadsworth SJ, Goldfine H.
Infect. Immun. 2002; 70: 4650-4660.
PMID 12117979
Differential localization of protein kinase C d by phorbol esters and related compounds using a fusion protein with green fluorescent protein.
Wang QJ, Bhattacharyya D, Garfield S, Nacro K, Marquez VE, Blumberg PM.
J. Biol. Chem. 1999; 274: 37233-37239.
PMID 10601287
Phosphoinositide-dependent protein kinase-1 (PDK1)-independent activation of the protein kinase C substrate, protein kinase D.
Wood CD, Kelly AP, Matthews SA, Cantrell DA.
FEBS Lett 2007; 581: 3494-3498.
PMID 17617409
Carbachol stimulates TYR phosphorylation and association of PKCd and PYK2 in pancreas.
Wrenn RW.
Biochem Biophys Res Commun 2001; 282: 882-886.
PMID 11352632
Activation of inwardly rectifying potassium (Kir) channels by phosphatidylinosital-4,5-bisphosphate (PIP2): interaction with other regulatory ligands.
Xie LH, John SA, Ribalet B, Weiss JN.
Prog Biophys Mol Biol 2007; 94: 320-335.
PMID 16837026
Protein kinase C delta activates IKB-kinase alpha to induce the p53 tumor suppressor in response to oxidative stress.
Yamaguchi T, Miki Y, Yoshida K.
Cell Signal 2007; 19: 2088-2097.
PMID 17644309
Clinical features, prognostic and risk factors of central nervous system infections in patients with systemic lupus erythematosus.
Yang CD, Wang XD, Ye S, Gu YY, Bao CD, Wang Y, Chen SL.
Clin Rheumatol 2007; 26: 895-901.
PMID 17021668
Protein Kinase C (d) Regulates Ser46 Phosphorylation of p53 Tumor Suppressor in the Apoptotic Response to DNA Damage.
Yoshida K, Liu H, Miki Y.
J Biol Chem 2006; 281: 5734-5740.
PMID 16377624
Protein kinase Cd is responsible for constitutive and DNA damage-induced phosphorylation of Rad9.
Yoshida K, Wang H, Miki Y, Kufe D.
EMBO J. 2003; 22: 1431-1441.
PMID 12628935
PKCd signaling: mechanisms of DNA damage response and apoptosis.
Yoshida K.
Cell Signal 2007; 19: 892-901.
PMID 17336499
Inhibition of histone acetyltransferase function of p300 by PKCd.
Yuan LW, Soh JW, Weinstein IB.
Biochim Biophys Acta 2002; 1592: 205-211.
PMID 12379484
Activation of protein kinase C PKCd by the c-Abl tyrosine kinase in response to ionizing radiation.
Yuan ZM, Utsugisawa T, Ishiko T, Nakada S, Huang Y, Kharbanda S, Weichselbaum R, Kufe D.
Oncogene 1998; 16: 1643-1648.
PMID 9582011
Comparative toxicokinetics of manganese chloride and methylcyclopentadienyl manganese tricarbonyl (MMT) in sprague-dawley rats.
Zheng W, Kim H, Zhao Q.
Toxicol Sci 2000; 54: 295-301.
PMID 10774811
Rapamycin-sensitive phosphorylation of PKC on a carboxy-terminal site by an atypical PKC complex.
Ziegler WH, Parekh DB, Le Good JA, Whelan RD, Kelly JJ, Frech M, Hemmings BA, Parker PJ.
Curr Biol 1999; 9: 522-529.
PMID 10339425

6. Citation

This paper should be referenced as such :
Malavez, Y ; Gonzalez-Mejia, ME ; Doseff, AI
PRKCD (protein kinase C, delta)
Atlas Genet Cytogenet Oncol Haematol. 2009;13(1):28-42.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 3 ]
  CACNA1D/PRKCD (3p21)
t(3;11)(p21;q13) LAMTOR1/PRKCD
t(3;12)(p21;q13) RDH5/PRKCD

7. External links

HGNC (Hugo)PRKCD   9399
Entrez_Gene (NCBI)PRKCD  5580  protein kinase C delta
AliasesALPS3; CVID9; MAY1; PKCD; 
GeneCards (Weizmann)PRKCD
Ensembl hg19 (Hinxton)ENSG00000163932 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000163932 [Gene_View] &nbspENSG00000163932 [Sequence]  chr3:53161207-53192717 [Contig_View]  PRKCD [Vega]
ICGC DataPortalENSG00000163932
Genatlas (Paris)PRKCD
Genetics Home Reference (NIH)PRKCD
Genomic and cartography
GoldenPath hg38 (UCSC)PRKCD  -     chr3:53161207-53192717 +  3p21.1   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)PRKCD  -     3p21.1   [Description]    (hg19-Feb_2009)
EnsemblPRKCD - 3p21.1 [CytoView hg19]  PRKCD - 3p21.1 [CytoView hg38]
Mapping of homologs : NCBIPRKCD [Mapview hg19]  PRKCD [Mapview hg38]
OMIM176977   615559   
Gene and transcription
Genbank (Entrez)AK130150 AK131548 AK294272 AK313216 AW293041
RefSeq transcript (Entrez)NM_001316327 NM_001354676 NM_001354678 NM_001354679 NM_001354680 NM_006254 NM_212539
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)PRKCD
Cluster EST : UnigeneHs.155342 [ NCBI ]
CGAP (NCI)Hs.155342
Alternative Splicing GalleryENSG00000163932
Gene Expression Viewer (FireBrowse)PRKCD [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets] &nbsp [Normal Tissue Atlas] &nbsp[carcinoma Classsification] &nbsp[NCI60]
GenevestigatorExpression in : [tissues] &nbsp[cell-lines] &nbsp[cancer] &nbsp[perturbations] &nbsp
BioGPS (Tissue expression)5580
GTEX Portal (Tissue expression)PRKCD
Human Protein AtlasENSG00000163932-PRKCD [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ05655   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ05655  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ05655
Splice isoforms : SwissVarQ05655
Catalytic activity : Enzyme2.7.10.2 [ Enzyme-Expasy ] [ IntEnz-EBI ] [ BRENDA ] [ KEGG ]   
Domaine pattern : Prosite (Expaxy)AGC_KINASE_CTER (PS51285)    PROTEIN_KINASE_ATP (PS00107)    PROTEIN_KINASE_DOM (PS50011)    PROTEIN_KINASE_ST (PS00108)    ZF_DAG_PE_1 (PS00479)    ZF_DAG_PE_2 (PS50081)   
Domains : Interpro (EBI)AGC-kinase_C    C2_domain_sf    DAG/PE-bd    Kinase-like_dom_sf    nPKC_delta    PE/DAG-bd    PKC_delta    Pkinase_C    Prot_kin_PKC_delta    Prot_kinase_dom    Protein_kinase_ATP_BS    Ser/Thr_kinase_AS   
Domain families : Pfam (Sanger)C1_1 (PF00130)    Pkinase (PF00069)    Pkinase_C (PF00433)   
Domain families : Pfam (NCBI)pfam00130    pfam00069    pfam00433   
Domain families : Smart (EMBL)C1 (SM00109)  S_TK_X (SM00133)  S_TKc (SM00220)  
Conserved Domain (NCBI)PRKCD
DMDM Disease mutations5580
Blocks (Seattle)PRKCD
PDB Europe1YRK    2YUU   
PDB (PDBSum)1YRK    2YUU   
PDB (IMB)1YRK    2YUU   
Structural Biology KnowledgeBase1YRK    2YUU   
SCOP (Structural Classification of Proteins)1YRK    2YUU   
CATH (Classification of proteins structures)1YRK    2YUU   
Human Protein Atlas [tissue]ENSG00000163932-PRKCD [tissue]
Peptide AtlasQ05655
IPIIPI00329236   IPI00945682   IPI00945961   IPI00946865   
Protein Interaction databases
IntAct (EBI)Q05655
Ontologies - Pathways
Ontology : AmiGOstimulatory C-type lectin receptor signaling pathway  protein kinase activity  protein serine/threonine kinase activity  protein serine/threonine kinase activity  protein serine/threonine kinase activity  protein serine/threonine kinase activity  protein kinase C activity  protein kinase C activity  calcium-independent protein kinase C activity  calcium-independent protein kinase C activity  non-membrane spanning protein tyrosine kinase activity  protein binding  ATP binding  extracellular region  nucleus  nucleoplasm  cytoplasm  endoplasmic reticulum  cytosol  cytosol  plasma membrane  plasma membrane  cell-cell junction  protein phosphorylation  apoptotic process  cell cycle  signal transduction  enzyme activator activity  intrinsic apoptotic signaling pathway in response to oxidative stress  regulation of signaling receptor activity  immunoglobulin mediated immune response  nuclear matrix  histone phosphorylation  peptidyl-serine phosphorylation  peptidyl-serine phosphorylation  peptidyl-threonine phosphorylation  peptidyl-tyrosine phosphorylation  enzyme binding  enzyme binding  kinase binding  protein kinase binding  termination of signal transduction  platelet activation  negative regulation of actin filament polymerization  positive regulation of endodeoxyribonuclease activity  negative regulation of protein binding  activation of protein kinase activity  interleukin-10 production  interleukin-12 production  positive regulation of superoxide anion generation  regulation of actin cytoskeleton organization  negative regulation of glial cell apoptotic process  positive regulation of protein dephosphorylation  intracellular signal transduction  azurophil granule lumen  Fc-gamma receptor signaling pathway involved in phagocytosis  B cell proliferation  neutrophil activation  positive regulation of protein import into nucleus  defense response to bacterium  neutrophil degranulation  negative regulation of MAP kinase activity  regulation of mRNA stability  insulin receptor substrate binding  negative regulation of insulin receptor signaling pathway  negative regulation of insulin receptor signaling pathway  metal ion binding  perinuclear region of cytoplasm  negative regulation of inflammatory response  negative regulation of peptidyl-tyrosine phosphorylation  protein stabilization  negative regulation of filopodium assembly  cell chemotaxis  interferon-gamma-mediated signaling pathway  extracellular exosome  cellular response to hydrogen peroxide  cellular response to hydroperoxide  negative regulation of platelet aggregation  cellular senescence  positive regulation of phospholipid scramblase activity  cellular response to angiotensin  positive regulation of ceramide biosynthetic process  positive regulation of glucosylceramide catabolic process  positive regulation of sphingomyelin catabolic process  positive regulation of response to DNA damage stimulus  positive regulation of apoptotic signaling pathway  
Ontology : EGO-EBIstimulatory C-type lectin receptor signaling pathway  protein kinase activity  protein serine/threonine kinase activity  protein serine/threonine kinase activity  protein serine/threonine kinase activity  protein serine/threonine kinase activity  protein kinase C activity  protein kinase C activity  calcium-independent protein kinase C activity  calcium-independent protein kinase C activity  non-membrane spanning protein tyrosine kinase activity  protein binding  ATP binding  extracellular region  nucleus  nucleoplasm  cytoplasm  endoplasmic reticulum  cytosol  cytosol  plasma membrane  plasma membrane  cell-cell junction  protein phosphorylation  apoptotic process  cell cycle  signal transduction  enzyme activator activity  intrinsic apoptotic signaling pathway in response to oxidative stress  regulation of signaling receptor activity  immunoglobulin mediated immune response  nuclear matrix  histone phosphorylation  peptidyl-serine phosphorylation  peptidyl-serine phosphorylation  peptidyl-threonine phosphorylation  peptidyl-tyrosine phosphorylation  enzyme binding  enzyme binding  kinase binding  protein kinase binding  termination of signal transduction  platelet activation  negative regulation of actin filament polymerization  positive regulation of endodeoxyribonuclease activity  negative regulation of protein binding  activation of protein kinase activity  interleukin-10 production  interleukin-12 production  positive regulation of superoxide anion generation  regulation of actin cytoskeleton organization  negative regulation of glial cell apoptotic process  positive regulation of protein dephosphorylation  intracellular signal transduction  azurophil granule lumen  Fc-gamma receptor signaling pathway involved in phagocytosis  B cell proliferation  neutrophil activation  positive regulation of protein import into nucleus  defense response to bacterium  neutrophil degranulation  negative regulation of MAP kinase activity  regulation of mRNA stability  insulin receptor substrate binding  negative regulation of insulin receptor signaling pathway  negative regulation of insulin receptor signaling pathway  metal ion binding  perinuclear region of cytoplasm  negative regulation of inflammatory response  negative regulation of peptidyl-tyrosine phosphorylation  protein stabilization  negative regulation of filopodium assembly  cell chemotaxis  interferon-gamma-mediated signaling pathway  extracellular exosome  cellular response to hydrogen peroxide  cellular response to hydroperoxide  negative regulation of platelet aggregation  cellular senescence  positive regulation of phospholipid scramblase activity  cellular response to angiotensin  positive regulation of ceramide biosynthetic process  positive regulation of glucosylceramide catabolic process  positive regulation of sphingomyelin catabolic process  positive regulation of response to DNA damage stimulus  positive regulation of apoptotic signaling pathway  
Pathways : KEGGChemokine signaling pathway    Vascular smooth muscle contraction    Tight junction    Fc epsilon RI signaling pathway    Fc gamma R-mediated phagocytosis    Neurotrophin signaling pathway    GnRH signaling pathway    Estrogen signaling pathway    Type II diabetes mellitus   
REACTOMEQ05655 [protein]
REACTOME PathwaysR-HSA-877300 [pathway]   
Atlas of Cancer Signalling NetworkPRKCD
Wikipedia pathwaysPRKCD
Orthology - Evolution
GeneTree (enSembl)ENSG00000163932
Phylogenetic Trees/Animal Genes : TreeFamPRKCD
Homologs : HomoloGenePRKCD
Homology/Alignments : Family Browser (UCSC)PRKCD
Gene fusions - Rearrangements
Fusion : MitelmanCACNA1D/PRKCD [3p21.1/3p21.1] &nbsp[t(3;3)(p21;p21)]  
Fusion : MitelmanLAMTOR1/PRKCD [11q13.4/3p21.1] &nbsp[ins(11;3)(q13;p13p21)]  
Fusion : MitelmanRDH5/PRKCD [12q13.2/3p21.1] &nbsp[t(3;12)(p21;q13)]  
Fusion PortalCACNA1D 3p21.1 PRKCD 3p21.1 BRCA
Fusion : QuiverPRKCD
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerPRKCD [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)PRKCD
Exome Variant ServerPRKCD
ExAC (Exome Aggregation Consortium)ENSG00000163932
GNOMAD BrowserENSG00000163932
Varsome BrowserPRKCD
Genetic variants : HAPMAP5580
Genomic Variants (DGV)PRKCD [DGVbeta]
DECIPHERPRKCD [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisPRKCD 
ICGC Data PortalPRKCD 
TCGA Data PortalPRKCD 
Broad Tumor PortalPRKCD
OASIS PortalPRKCD [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICPRKCD  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDPRKCD
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch PRKCD
DgiDB (Drug Gene Interaction Database)PRKCD
DoCM (Curated mutations)PRKCD (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)PRKCD (select a term)
NCG5 (London)PRKCD
Cancer3DPRKCD(select the gene name)
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
OMIM176977    615559   
Orphanet3469    3468    21114   
Genetic Testing Registry PRKCD
NextProtQ05655 [Medical]
Target ValidationPRKCD
Huge Navigator PRKCD [HugePedia]
snp3D : Map Gene to Disease5580
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD5580
Chemical/Pharm GKB GenePA33763
Clinical trialPRKCD
canSAR (ICR)PRKCD (select the gene name)
DataMed IndexPRKCD
Other database
Other database
Other database
Other database
Other databaseδ.html
Other database
Other database
Other database
PubMed499 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

Search in all EBI   NCBI

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indexed on : Thu Jan 17 19:05:25 CET 2019

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