RAP1GAP (RAP1 GTPase activating protein)

Written2010-01Zixing Chen, Xuejun Shao
Jiangsu Institute of Hematology, 1st Affiliated Hospital, Soochow University, Suzhou 215006 JS, China

(Note : for Links provided by Atlas : click)

1. Identity

General Information
Alias_symbol (synonym)KIAA0474
Other aliasRAPGAP
LocusID (NCBI) 5909
Atlas_Id 42043
Location 1p36.12  [Link to chromosome band 1p36]
Location_base_pair Starts at 21596221 and ends at 21669380 bp from pter ( according to hg19-Feb_2009)  [Mapping RAP1GAP.png]
Local_order From centromere to telomere: NBPF3, ALPL, RAP1GAP, USP48, HSPG2.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
EIF4G3 (1p36.12) / RAP1GAP (1p36.12)RAP1GAP (1p36.12) / GLIS3 (9p24.2)RAP1GAP (1p36.12) / GOLGB1 (3q13.33)
RAP1GAP (1p36.12) / NIT2 (3q12.2)RAP1GAP (1p36.12) / USP48 (1p36.12)


Description 25 exons encompassing about 73 kb of genomic DNA.
Transcription About 3.334 kb mRNA, and has three transcript variant, RAP1 GTPase activating protein isoform a, b, c.

3. Protein

Description 663 amino acids; homodimer and heterodimer with RAP1B.
Expression Significant expression seen in the brain, kidney and pancreas. Abundant in the cerebral cortex and expressed at much lower levels in the spinal cord. Not detected in the lymphoid tissues. (according to Swiss-Prot).
Localisation Golgi apparatus membrane; Peripheral membrane protein (according to Swiss-Prot).
Function GTPase activator for the nuclear Ras-related regulatory protein Rap1, converting it to the putatively inactive GDP-bound state (according to Swiss-Prot); Regulation of small GTPase-mediated signal transduction.
Homology The RAP1GAP gene is conserved in cow, mouse, rat, zebrafish, fruit fly, mosquito, and C. elegans.

4. Implicated in

Entity Solid tumors
Disease Papillary thyroid cancer, pancreatic cancer, prostate cancer, melanoma tumors
Oncogenesis Rap1GAP, which acts as a GTPase activator for the nuclear Ras-related regulatory protein Rap1, was a specific negative regulator of Rap1, and the monomeric G protein Rap1 has been implicated in cancer tumorigenesis. It signals to pathways involved in cell adhesion, migration, and survival. Loss of Rap1GAP was discovered in papillary thyroid cancer, pancreatic cancer, prostate cancer, melanoma tumors, and their cell lines, all of them exhibited increased Rap1 activity, that activation of Rap1 promotes cell proliferation and migration potentiality through the mitogen-activated protein kinase pathway and integrin activation. As a putative tumor suppressor gene, Rap1GAP inhibits tumor growth but induces MMP2- and MMP9-mediated squamous cell carcinoma invasion and tumor progression, suggesting a role for this protein as a biomarker for early N-stage, aggressive squamous cell carcinomas.
Entity Myelodysplastic syndrome (MDS)
Disease The expression level of Rap1GAP in MDS patients significantly increased as compared with patients with non-malignant blood diseases or acute myeloid leukemia (AML). Among MDS patients, the expression level of Rap1GAP in MDS-refractory anemia (RA) was significantly higher than that in MDS-refractory anemia with excess of blasts (RAEB).
On the other hand, inhibiting Rap1 activity by expression of Rap1GAP increased leukocyte transendothelial migration, providing physiological relevance to the hypothesis that Rap1 augments barrier function of inter-endothelial cell junctions, implying the relevance of Rap1GAP in the regulation of haematogenesis.

5. Bibliography

Activation of Rap1 promotes prostate cancer metastasis.
Bailey CL, Kelly P, Casey PJ.
Cancer Res. 2009 Jun 15;69(12):4962-8. Epub 2009 May 26.
PMID 19470770
Protein RAP1GAP in human myelodysplastic syndrome detected by flow cytometry and its clinical relevance.
Ika SA, Qi XF, Chen ZX.
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2009 Jun;17(3):612-7.
PMID 19549374
Rap1GAP promotes invasion via induction of matrix metalloproteinase 9 secretion, which is associated with poor survival in low N-stage squamous cell carcinoma.
Mitra RS, Goto M, Lee JS, Maldonado D, Taylor JM, Pan Q, Carey TE, Bradford CR, Prince ME, Cordell KG, Kirkwood KL, D'Silva NJ.
Cancer Res. 2008 May 15;68(10):3959-69.
PMID 18483282
Loss of Rap1GAP in papillary thyroid cancer.
Nellore A, Paziana K, Ma C, Tsygankova OM, Wang Y, Puttaswamy K, Iqbal AU, Franks SR, Lv Y, Troxel AB, Feldman MD, Meinkoth JL, Brose MS.
J Clin Endocrinol Metab. 2009 Mar;94(3):1026-32. Epub 2008 Dec 9.
PMID 19066305
Expression of Rap1GAP in human myeloid disease following microarray selection.
Qi X, Chen Z, Qian J, Cen J, Gu M.
Genet Mol Res. 2008 Apr 29;7(2):379-87.
PMID 18551404
Rap1 GTPase inhibits leukocyte transmigration by promoting endothelial barrier function.
Wittchen ES, Worthylake RA, Kelly P, Casey PJ, Quilliam LA, Burridge K.
J Biol Chem. 2005 Mar 25;280(12):11675-82. Epub 2005 Jan 20.
PMID 15661741
Identification of a putative tumor suppressor gene Rap1GAP in pancreatic cancer.
Zhang L, Chenwei L, Mahmood R, van Golen K, Greenson J, Li G, D'Silva NJ, Li X, Burant CF, Logsdon CD, Simeone DM.
Cancer Res. 2006 Jan 15;66(2):898-906.
PMID 16424023
Rap1GAP inhibits tumor growth in oropharyngeal squamous cell carcinoma.
Zhang Z, Mitra RS, Henson BS, Datta NS, McCauley LK, Kumar P, Lee JS, Carey TE, D'Silva NJ.
Am J Pathol. 2006 Feb;168(2):585-96.
PMID 16436672
Down-regulation of Rap1GAP via promoter hypermethylation promotes melanoma cell proliferation, survival, and migration.
Zheng H, Gao L, Feng Y, Yuan L, Zhao H, Cornelius LA.
Cancer Res. 2009 Jan 15;69(2):449-57.
PMID 19147557

6. Citation

This paper should be referenced as such :
Chen, Z ; Shao, X
RAP1GAP (RAP1 GTPase activating protein)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(11):1034-1035.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://atlasgeneticsoncology.usal.es/classic/Genes/RAP1GAPID42043ch1p36.html

Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 4 ]
  EIF4G3/RAP1GAP (1p36)
RAP1GAP/USP48 (1p36)
t(1;3)(p36;q12) RAP1GAP/NIT2
t(1;3)(p36;q13) RAP1GAP/GOLGB1

7. External links

HGNC (Hugo)RAP1GAP   9858
Entrez_Gene (NCBI)RAP1GAP  5909  RAP1 GTPase activating protein
GeneCards (Weizmann)RAP1GAP
Ensembl hg19 (Hinxton)ENSG00000076864 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000076864 [Gene_View] &nbspENSG00000076864 [Sequence]  chr1:21596221-21669380 [Contig_View]  RAP1GAP [Vega]
ICGC DataPortalENSG00000076864
Genatlas (Paris)RAP1GAP
Genetics Home Reference (NIH)RAP1GAP
Genomic and cartography
GoldenPath hg38 (UCSC)RAP1GAP  -     chr1:21596221-21669380 -  1p36.12   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)RAP1GAP  -     1p36.12   [Description]    (hg19-Feb_2009)
EnsemblRAP1GAP - 1p36.12 [CytoView hg19]  RAP1GAP - 1p36.12 [CytoView hg38]
Mapping of homologs : NCBIRAP1GAP [Mapview hg19]  RAP1GAP [Mapview hg38]
Gene and transcription
Genbank (Entrez)AB003930 AB007943 AF114047 AI301600 AI827348
RefSeq transcript (Entrez)NM_001145657 NM_001145658 NM_001330383 NM_001350524 NM_001350525 NM_001350526 NM_001350527 NM_001350528 NM_002885
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)RAP1GAP
Cluster EST : UnigeneHs.148178 [ NCBI ]
CGAP (NCI)Hs.148178
Alternative Splicing GalleryENSG00000076864
Gene Expression Viewer (FireBrowse)RAP1GAP [ 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)5909
GTEX Portal (Tissue expression)RAP1GAP
Human Protein AtlasENSG00000076864-RAP1GAP [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP47736   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP47736  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP47736
Splice isoforms : SwissVarP47736
Domaine pattern : Prosite (Expaxy)GOLOCO (PS50877)    RAPGAP (PS50085)   
Domains : Interpro (EBI)GoLoco_motif    Rap/Ran-GAP_sf    Rap_GAP_dom   
Domain families : Pfam (Sanger)GoLoco (PF02188)    Rap_GAP (PF02145)   
Domain families : Pfam (NCBI)pfam02188    pfam02145   
Domain families : Smart (EMBL)GoLoco (SM00390)  
Conserved Domain (NCBI)RAP1GAP
DMDM Disease mutations5909
Blocks (Seattle)RAP1GAP
PDB Europe1SRQ    3BRW   
PDB (PDBSum)1SRQ    3BRW   
PDB (IMB)1SRQ    3BRW   
Structural Biology KnowledgeBase1SRQ    3BRW   
SCOP (Structural Classification of Proteins)1SRQ    3BRW   
CATH (Classification of proteins structures)1SRQ    3BRW   
Human Protein Atlas [tissue]ENSG00000076864-RAP1GAP [tissue]
Peptide AtlasP47736
IPIIPI00843926   IPI00386930   IPI01013142   IPI00872409   IPI00981523   IPI00980108   IPI00873409   IPI00646110   IPI00514768   
Protein Interaction databases
IntAct (EBI)P47736
Ontologies - Pathways
Ontology : AmiGOGolgi membrane  GTPase activity  GTPase activator activity  GTPase activator activity  protein binding  cytosol  cytosol  signal transduction  axon guidance  membrane  Ras GTPase binding  protein homodimerization activity  regulation of GTPase activity  positive regulation of GTPase activity  regulation of small GTPase mediated signal transduction  negative regulation of microvillus assembly  
Ontology : EGO-EBIGolgi membrane  GTPase activity  GTPase activator activity  GTPase activator activity  protein binding  cytosol  cytosol  signal transduction  axon guidance  membrane  Ras GTPase binding  protein homodimerization activity  regulation of GTPase activity  positive regulation of GTPase activity  regulation of small GTPase mediated signal transduction  negative regulation of microvillus assembly  
Pathways : KEGGRap1 signaling pathway   
REACTOMEP47736 [protein]
REACTOME PathwaysR-HSA-8853659 [pathway]   
Atlas of Cancer Signalling NetworkRAP1GAP
Wikipedia pathwaysRAP1GAP
Orthology - Evolution
GeneTree (enSembl)ENSG00000076864
Phylogenetic Trees/Animal Genes : TreeFamRAP1GAP
Homologs : HomoloGeneRAP1GAP
Homology/Alignments : Family Browser (UCSC)RAP1GAP
Gene fusions - Rearrangements
Fusion : MitelmanEIF4G3/RAP1GAP [1p36.12/1p36.12] &nbsp[t(1;1)(p36;p36)]  
Fusion : MitelmanRAP1GAP/GOLGB1 [1p36.12/3q13.33] &nbsp[t(1;3)(p36;q13)]  
Fusion : MitelmanRAP1GAP/NIT2 [1p36.12/3q12.2] &nbsp[t(1;3)(p36;q12)]  
Fusion : MitelmanRAP1GAP/USP48 [1p36.12/1p36.12] &nbsp[t(1;1)(p36;p36)]  
Fusion PortalEIF4G3 1p36.12 RAP1GAP 1p36.12 BRCA
Fusion PortalRAP1GAP 1p36.12 GOLGB1 3q13.33 PRAD
Fusion PortalRAP1GAP 1p36.12 NIT2 3q12.2 BRCA
Fusion PortalRAP1GAP 1p36.12 USP48 1p36.12 BRCA
Fusion : QuiverRAP1GAP
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerRAP1GAP [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)RAP1GAP
Exome Variant ServerRAP1GAP
ExAC (Exome Aggregation Consortium)ENSG00000076864
GNOMAD BrowserENSG00000076864
Varsome BrowserRAP1GAP
Genetic variants : HAPMAP5909
Genomic Variants (DGV)RAP1GAP [DGVbeta]
DECIPHERRAP1GAP [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisRAP1GAP 
ICGC Data PortalRAP1GAP 
TCGA Data PortalRAP1GAP 
Broad Tumor PortalRAP1GAP
OASIS PortalRAP1GAP [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICRAP1GAP  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDRAP1GAP
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 RAP1GAP
DgiDB (Drug Gene Interaction Database)RAP1GAP
DoCM (Curated mutations)RAP1GAP (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)RAP1GAP (select a term)
NCG5 (London)RAP1GAP
Cancer3DRAP1GAP(select the gene name)
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Genetic Testing Registry RAP1GAP
NextProtP47736 [Medical]
Target ValidationRAP1GAP
Huge Navigator RAP1GAP [HugePedia]
snp3D : Map Gene to Disease5909
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD5909
Chemical/Pharm GKB GenePA34220
Clinical trialRAP1GAP
canSAR (ICR)RAP1GAP (select the gene name)
DataMed IndexRAP1GAP
PubMed69 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

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Thu Jan 17 19:06:22 CET 2019

For comments and suggestions or contributions, please contact us atlasgeneticsoncology@usal.es.