SHC4 (SHC (Src homology 2 domain containing) family, member 4)

Written2009-09Luigi Pasini, Luisa Lanfrancone
IEO, European Institute of Oncology, Department of Experimental Oncology, IFOM-IEO Campus, Via Adamello 16, 20139 Milano, Italy

(Note : for Links provided by Atlas : click)

1. Identity

General Information
Alias_symbol (synonym)RaLP
Other aliasMGC34023
HGNC (Hugo) SHC4
LocusID (NCBI) 399694
Atlas_Id 44503
Location 15q21.1  [Link to chromosome band 15q21]
Location_base_pair Starts at 48823737 and ends at 48963444 bp from pter ( according to hg19-Feb_2009)  [Mapping SHC4.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)
MYO5C (15q21.2) / SHC4 (15q21.1)SHC4 (15q21.1) / AKR1C8P (-)SHC4 (15q21.1) / B3GAT3 (11q12.3)
SHC4 (15q21.1) / RANGAP1 (22q13.2)SHC4 (15q21.1) / SHC4 (15q21.1)
Note The mammalian Src homology and collagen (SHC) gene family comprises four distinct loci that encode proteins sharing a unique structural organization. SHC proteins function as phosphotyrosine-binding docking molecule mediating the signaling transduction of cell-membrane receptors, including receptor tyrosine kinases (RTKs). SHC proteins display mutually exclusive tissue localization. SHC1 is ubiquitously expressed except than in the nervous system, while SHC2 and SHC3 are specifically found in the brain. SHC4 is the latest member being identified and its expression is restricted to brain and skeletal muscle of adult mice, whereas in human it appears primarily expressed in melanoma tissues and cell lines of melanocytic origin.


  Genomic position of the human SHC4 locus, situated on the long arm (q21.1-q21.2) of chromosome 15. The DNA sequence containing the SHC4 gene also codifies for the short unrelated transcript EID1.
Description Human SHC4 locus spans 139,707 bases on chromosome 15, starting at position 46,903,227 bp and ending at position 47,042,933 from pter (according to hg18-Mar-2006). The same locus that codifies for SHC4 transcript also produces the small and unrelated protein EP300 interacting inhibitor of differentiation 1 (EID1) that has been found only in the mammalian genome. Orthologs of SHC4 are present in other metazoan. The corresponding mouse gene is located on chromosome 2F1.
Transcription Both human and mouse SHC4 open reading frame consist of twelve exons, producing nucleotide sequences of 1893 nt and 1881 nt respectively that encode for putative polypeptides of 630 amino acids in human and 626 amino acids in mouse. No clear evidence of alternative splicing isoforms of the main mRNA transcript has been found so far.
Pseudogene None identified.

3. Protein

  SHC4 shares the same genomic architecture and protein organization typical of the SHC family. Evolutionarily conserved phosphotyrosine sites in the collagen homology 1 (CH1) region are marked in blue. Green boxes identify exons; bent arrow highlights the first ATG codon.
Description The amino-terminal positioning of the phosphotyrosine-binding (PTB) domain and the carbossi-terminal positioning of the Src homology 2 (SH2) domain is a hallmark of the SHC family. These two domains are divided by the CH1 region, which contains three highly conserved tyrosine residues. A second collagen homology (CH2) region is present in the longest isoforms of the Shc family members and in SHC4. The human SHC4 protein consists of 630 amino acids with a total estimated molecular weight of 69 KDa. Although no splicing isoform are known, it is postulated that two other polypeptides may be produced by the usage of alternate initiator codons, corresponding to predicted products of 59 KDa and 49 KDa.
Expression Human SHC4 shows a specific expression in advanced-stage melanomas and in no other human normal and tumoral adult tissues. SHC4 protein product is detected in primary cultures and cell lines of metastatic melanoma, while its expression decreases in non-invasive melanoma cell lines and in primary melanocytes. In adult mouse tissues SHC4 is primarily detected in brain and skeletal muscle.
Localisation In humans, SHC4 protein is mostly localized in the cytosol of melanocytes and melanoma cells and partly to cell membranes. The murine SHC4 protein was demonstrated to co-localize with muscle-specific kinase (MuSK) at the postsynaptic neuromuscular junction (NMJ).
Function SHC4 is a substrate of several receptor tyrosine kinases (RTK) and G protein-coupled receptors (GPCR). When ectopically expressed in non-metastatic melanoma cell lines SHC4 becomes phosphorylated upon growth factor stimulation and associates with the growth factor receptor-bound protein 2 (Grb2). Tyrosine-phosphorylated SHC4 induces Ras GTPase and mitogen activated protein kinase (MAPK) activation, resulting in enhanced cell migration. Conversely, silencing of SHC4 expression in metastatic melanoma cells reduces migration without affecting MAPK pathway, suggesting that SHC4 may participate in both Ras - dependent and - independent pathways in human melanoma. SHC4 appears to be important for the regulation of postsynaptic signals of motoneurons through association with MuSK and activation of acetylcholine receptors (AChR), as indicated by biochemical studies of the mouse protein.
Homology Among all the human paralogous genes, SHC4 shares an overall identity at protein level of 45%, 37% and 41% with SHC1, SHC2, and SHC3 respectively. The highest conservation is detected in the PTB and SH2 regions. Human and murine SHC4 display 75% sequence identity in both the PTB and SH2 domains.

4. Implicated in

Entity Melanoma
Disease Melanoma is an extremely aggressive cancer of the skin and of the internal mucosa that is capable of metastasizing in almost every site of the body. Patients with an advanced-stage melanoma are at greater risk of dying of their melanoma.
Prognosis The more reliable prognostic parameters in melanoma are the Breslow measurement and the Clark level. The Breslow index measures the thickness of the melanoma: the thinner the melanoma, the better the prognosis. In general, melanomas less than 1 millimeter (mm) in depth have a very small chance of spreading and then invading. The Clark level describes how far a melanoma has penetrated into the skin, using a scale of I to V (with higher numbers indicating a deeper melanoma). According to Clark's model, cutaneous melanoma initially develops from an in situ growth to a radial growth phase (RGP) and evolves into the vertical growth phase (VGP), which is associated to an increased risk of metastatization.
Oncogenesis The RGP melanoma expands radially into the epidermis and proceeds to the VGP phase invading the dermis, before becoming metastatic. Analysis of a cohort of human melanoma lesions at various stages of the disease revealed that SHC4 expression is found in around 50% of the VGP and metastatic melanomas and not in nevi and RGP melanomas, thus suggesting a putative role for SHC4 as a prognostic marker. When SHC4 is ectopically overexpressed in RGP melanoma cells it can stimulate migration in vitro, without perturbing proliferation. Conversely, SHC4 silencing in metastatic melanoma cell lines inhibits migration and delays tumor formation in vivo, suggesting that SHC4 is important for the invasive potential of melanoma cells.

5. Bibliography

RaLP, a new member of the Src homology and collagen family, regulates cell migration and tumor growth of metastatic melanomas.
Fagiani E, Giardina G, Luzi L, Cesaroni M, Quarto M, Capra M, Germano G, Bono M, Capillo M, Pelicci P, Lanfrancone L.
Cancer Res. 2007 Apr 1;67(7):3064-73.
PMID 17409413
Analysis of a Shc family adaptor protein, ShcD/Shc4, that associates with muscle-specific kinase.
Jones N, Hardy WR, Friese MB, Jorgensen C, Smith MJ, Woody NM, Burden SJ, Pawson T.
Mol Cell Biol. 2007 Jul;27(13):4759-73. Epub 2007 Apr 23.
PMID 17452444
Melanoma: targeting signaling pathways and RaLP.
Pasini L, Turco MY, Luzi L, Aladowicz E, Fagiani E, Lanfrancone L.
Expert Opin Ther Targets. 2009 Jan;13(1):93-104.
PMID 19063709

6. Citation

This paper should be referenced as such :
Pasini, L ; Lanfrancone, L
SHC4 (SHC (Src homology 2 domain containing) family, member 4)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(8):732-734.
Free journal version : [ pdf ]   [ DOI ]
On line version :

7. External links

HGNC (Hugo)SHC4   16743
Entrez_Gene (NCBI)SHC4  399694  SHC adaptor protein 4
AliasesRaLP; SHCD
GeneCards (Weizmann)SHC4
Ensembl hg19 (Hinxton)ENSG00000185634 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000185634 [Gene_View] &nbspENSG00000185634 [Sequence]  chr15:48823737-48963444 [Contig_View]  SHC4 [Vega]
ICGC DataPortalENSG00000185634
TCGA cBioPortalSHC4
AceView (NCBI)SHC4
Genatlas (Paris)SHC4
SOURCE (Princeton)SHC4
Genetics Home Reference (NIH)SHC4
Genomic and cartography
GoldenPath hg38 (UCSC)SHC4  -     chr15:48823737-48963444 -  15q21.1   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)SHC4  -     15q21.1   [Description]    (hg19-Feb_2009)
EnsemblSHC4 - 15q21.1 [CytoView hg19]  SHC4 - 15q21.1 [CytoView hg38]
Mapping of homologs : NCBISHC4 [Mapview hg19]  SHC4 [Mapview hg38]
Gene and transcription
Genbank (Entrez)AK124916 AK125762 AK302156 AW102644 AY358250
RefSeq transcript (Entrez)NM_203349
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)SHC4
Cluster EST : UnigeneHs.642615 [ NCBI ]
CGAP (NCI)Hs.642615
Alternative Splicing GalleryENSG00000185634
Gene ExpressionSHC4 [ NCBI-GEO ]   SHC4 [ EBI - ARRAY_EXPRESS ]   SHC4 [ SEEK ]   SHC4 [ MEM ]
Gene Expression Viewer (FireBrowse)SHC4 [ 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)399694
GTEX Portal (Tissue expression)SHC4
Human Protein AtlasENSG00000185634-SHC4 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ6S5L8   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ6S5L8  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ6S5L8
Splice isoforms : SwissVarQ6S5L8
Domaine pattern : Prosite (Expaxy)PID (PS01179)    SH2 (PS50001)   
Domains : Interpro (EBI)PH-like_dom_sf    PID_Shc-like    PTB/PI_dom    SH2    SH2_dom_sf    SHC4    SHC_SH2   
Domain families : Pfam (Sanger)PID (PF00640)    SH2 (PF00017)   
Domain families : Pfam (NCBI)pfam00640    pfam00017   
Domain families : Smart (EMBL)PTB (SM00462)  SH2 (SM00252)  
Conserved Domain (NCBI)SHC4
DMDM Disease mutations399694
Blocks (Seattle)SHC4
Human Protein Atlas [tissue]ENSG00000185634-SHC4 [tissue]
Peptide AtlasQ6S5L8
IPIIPI00217895   IPI00747728   IPI01010715   
Protein Interaction databases
IntAct (EBI)Q6S5L8
Ontologies - Pathways
Ontology : AmiGOprotein binding  plasma membrane  apoptotic process  positive regulation of cell proliferation  regulation of gene expression  protein domain specific binding  cell junction  receptor tyrosine kinase binding  intracellular signal transduction  postsynaptic membrane  stem cell differentiation  
Ontology : EGO-EBIprotein binding  plasma membrane  apoptotic process  positive regulation of cell proliferation  regulation of gene expression  protein domain specific binding  cell junction  receptor tyrosine kinase binding  intracellular signal transduction  postsynaptic membrane  stem cell differentiation  
Pathways : KEGGErbB signaling pathway    Ras signaling pathway    Chemokine signaling pathway    Focal adhesion    Natural killer cell mediated cytotoxicity    Neurotrophin signaling pathway    Insulin signaling pathway    Estrogen signaling pathway    Prolactin signaling pathway    Alcoholism    Bacterial invasion of epithelial cells    MicroRNAs in cancer    Glioma    Chronic myeloid leukemia   
NDEx NetworkSHC4
Atlas of Cancer Signalling NetworkSHC4
Wikipedia pathwaysSHC4
Orthology - Evolution
GeneTree (enSembl)ENSG00000185634
Phylogenetic Trees/Animal Genes : TreeFamSHC4
Homologs : HomoloGeneSHC4
Homology/Alignments : Family Browser (UCSC)SHC4
Gene fusions - Rearrangements
Fusion : QuiverSHC4
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerSHC4 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)SHC4
Exome Variant ServerSHC4
ExAC (Exome Aggregation Consortium)ENSG00000185634
GNOMAD BrowserENSG00000185634
Varsome BrowserSHC4
Genetic variants : HAPMAP399694
Genomic Variants (DGV)SHC4 [DGVbeta]
DECIPHERSHC4 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisSHC4 
ICGC Data PortalSHC4 
TCGA Data PortalSHC4 
Broad Tumor PortalSHC4
OASIS PortalSHC4 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICSHC4  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDSHC4
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 SHC4
DgiDB (Drug Gene Interaction Database)SHC4
DoCM (Curated mutations)SHC4 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)SHC4 (select a term)
NCG5 (London)SHC4
Cancer3DSHC4(select the gene name)
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Genetic Testing Registry SHC4
NextProtQ6S5L8 [Medical]
Target ValidationSHC4
Huge Navigator SHC4 [HugePedia]
snp3D : Map Gene to Disease399694
BioCentury BCIQSHC4
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD399694
Chemical/Pharm GKB GenePA142670917
Clinical trialSHC4
canSAR (ICR)SHC4 (select the gene name)
DataMed IndexSHC4
PubMed18 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Thu Jan 17 19:08:12 CET 2019

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