RAP1GAP (RAP1 GTPase activating protein)

2010-01-01   Zixing Chen , Xuejun Shao 

Jiangsu Institute of Hematology, 1st Affiliated Hospital, Soochow University, Suzhou 215006 JS, China

Identity

HGNC
LOCATION
1p36.12
LOCUSID
ALIAS
RAP1GA1,RAP1GAP1,RAP1GAPII,RAPGAP
FUSION GENES

DNA/RNA

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.

Proteins

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.

Implicated in

Entity name
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 name
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.

Bibliography

Pubmed IDLast YearTitleAuthors
194707702009Activation of Rap1 promotes prostate cancer metastasis.Bailey CL et al
195493742009Protein RAP1GAP in human myelodysplastic syndrome detected by flow cytometry and its clinical relevance.Ika SA et al
184832822008Rap1GAP promotes invasion via induction of matrix metalloproteinase 9 secretion, which is associated with poor survival in low N-stage squamous cell carcinoma.Mitra RS et al
190663052009Loss of Rap1GAP in papillary thyroid cancer.Nellore A et al
185514042008Expression of Rap1GAP in human myeloid disease following microarray selection.Qi X et al
156617412005Rap1 GTPase inhibits leukocyte transmigration by promoting endothelial barrier function.Wittchen ES et al
164240232006Identification of a putative tumor suppressor gene Rap1GAP in pancreatic cancer.Zhang L et al
164366722006Rap1GAP inhibits tumor growth in oropharyngeal squamous cell carcinoma.Zhang Z et al
191475572009Down-regulation of Rap1GAP via promoter hypermethylation promotes melanoma cell proliferation, survival, and migration.Zheng H et al

Other Information

Locus ID:

NCBI: 5909
MIM: 600278
HGNC: 9858
Ensembl: ENSG00000076864

Variants:

dbSNP: 5909
ClinVar: 5909
TCGA: ENSG00000076864
COSMIC: RAP1GAP

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000076864ENST00000290101A0A0A0MQY8
ENSG00000076864ENST00000317967Q5T3T1
ENSG00000076864ENST00000374761J3KPC5
ENSG00000076864ENST00000374763X6R8W7
ENSG00000076864ENST00000374765P47736
ENSG00000076864ENST00000374765A0A024RAB5
ENSG00000076864ENST00000447293Q5T3T0
ENSG00000076864ENST00000471600F2Z357
ENSG00000076864ENST00000495204P47736
ENSG00000076864ENST00000542643P47736

Expression (GTEx)

0
50
100
150
200
250
300
350

Pathways

PathwaySourceExternal ID
Rap1 signaling pathwayKEGGhsa04015
Rap1 signaling pathwayKEGGko04015
Immune SystemREACTOMER-HSA-168256
Adaptive Immune SystemREACTOMER-HSA-1280218
Rap1 signallingREACTOMER-HSA-392517
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
RET signalingREACTOMER-HSA-8853659

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
179546082007KRIT-1/CCM1 is a Rap1 effector that regulates endothelial cell cell junctions.137
146079722003Rap1 GTPase: functions, regulation, and malignancy.62
215326182011The tumor suppressor gene rap1GAP is silenced by miR-101-mediated EZH2 overexpression in invasive squamous cell carcinoma.50
156570462005Cannabinoid receptor-induced neurite outgrowth is mediated by Rap1 activation through G(alpha)o/i-triggered proteasomal degradation of Rap1GAPII.42
164240232006Identification of a putative tumor suppressor gene Rap1GAP in pancreatic cancer.42
191475572009Down-regulation of Rap1GAP via promoter hypermethylation promotes melanoma cell proliferation, survival, and migration.36
184832822008Rap1GAP promotes invasion via induction of matrix metalloproteinase 9 secretion, which is associated with poor survival in low N-stage squamous cell carcinoma.35
201244892010Downregulation of Rap1GAP through epigenetic silencing and loss of heterozygosity promotes invasion and progression of thyroid tumors.33
216331102011A mechanism of Rap1-induced stabilization of endothelial cell--cell junctions.31
164366722006Rap1GAP inhibits tumor growth in oropharyngeal squamous cell carcinoma.29

Citation

Zixing Chen ; Xuejun Shao

RAP1GAP (RAP1 GTPase activating protein)

Atlas Genet Cytogenet Oncol Haematol. 2010-01-01

Online version: http://atlasgeneticsoncology.org/gene/42043/rap1gap-(rap1-gtpase-activating-protein)