HGNC Approved Gene Symbol: RAP2B
Cytogenetic location: 3q25.2 Genomic coordinates (GRCh38): 3:153,162,226-153,170,627 (from NCBI)
Ohmstede et al. (1990) screened a platelet cDNA library with monoclonal antibody that recognizes a highly conserved epitope of Ras p21 (see 190020) involved in GTP binding. They identified a protein that is structurally and functionally similar to but distinct from RAP1A (179520), RAP1B (179530), and RAP2A (179540). RAP2B has a characteristic Ras-type C-terminal motif for polyisoprenylation, and 2 C-terminal cysteines suggesting that it may also be palmitoylated. Recombinant RAP2B had an apparent molecular mass of 22 kD. The deduced RAP2B protein contains 183 amino acids (Farrell et al., 1990). By RT-PCR, Greco et al. (2006) detected RAP2B in purified human reticulocytes. Western blot analysis of fractionated cells revealed the association of RAP2B with cell membranes.
Ohmstede et al. (1990) demonstrated that recombinant RAP2B bound GTP. By cell fractionated and Western blot analysis, Torti et al. (1993) found that RAB2B was detergent soluble in resting platelets, but a significant amount of RAP2B was associated with the cytoskeleton in platelets aggregated with thrombin (176930), a thromboxane analog, or a Ca(2+)-ATPase inhibitor. Translocation of RAP2B to the cytoskeleton was strictly dependent on platelet aggregation. Inhibition of fibrinogen (see FGA, 134820) binding to the glycoprotein IIb (607759)-IIIa (173470) complex completely prevented the interaction of RAP2B with the cytoskeleton.
Greco et al. (2006) found that membrane-associated RAP2B was activated upon treatment of normal human reticulocytes with calcium and a calcium ionophore. RAP2B was enriched in microvesicles released by calcium-activated reticulocytes, suggesting a role for RAP2B in membrane shedding.
Meng et al. (2018) identified the Ras-related GTPase RAP2, which is composed of 3 components, RAP2A, RAP2B, and RAP2C (301016), as a key intracellular signal transducer that relays extracellular matrix rigidity signals to control mechanosensitive cellular activities through YAP (606608) and TAZ (607392). RAP2 is activated by low extracellular matrix stiffness, and deletion of RAP2 blocks the regulation of YAP and TAZ by stiffness signals and promotes aberrant cell growth. Mechanistically, matrix stiffness acts through phospholipase C-gamma-1 (PLCG1; 172420) to influence levels of phosphatidylinositol 4,5-bisphosphate and phosphatidic acid, which activates RAP2 through PDZGEF1 (RAPGEF2; 609530) and PDZGEF2 (RAPGEF6; 610499). At low stiffness, active RAP2 binds to and stimulates MAP4K4 (604666), MAP4K6 (MINK1; 609426), MAP4K7, and ARHGAP29 (610496), resulting in activation of LATS1 (603473) and LATS2 (604861) and inhibition of YAP and TAZ. RAP2, YAP, and TAZ have pivotal roles in mechanoregulated transcription, as deletion of YAP and TAZ abolishes the extracellular matrix stiffness-responsive transcriptome. Meng et al. (2018) concluded that their findings showed that RAP2 is a molecular switch in mechanotransduction, thereby defining a mechanosignaling pathway from extracellular membrane stiffness to the nucleus.
Stumpf (2024) mapped the RAP2B gene to chromosome 3q25.2 based on an alignment of the RAP2B sequence (GenBank AF493915) with the genomic sequence (GRCh38).
Farrell, F. X., Ohmstede, C.-A., Reep, B. R., Lapetina, E. G. cDNA sequence of a new ras-related gene (rap2b) isolated from human platelets with sequence homology to rap2. Nucleic Acids Res. 18: 4281 only, 1990. [PubMed: 2115998] [Full Text: https://doi.org/10.1093/nar/18.14.4281]
Greco, F., Ciana, A., Pietra, D., Balduini, C., Minetti, G., Torti, M. Rap2, but not Rap1 GTPase is expressed in human red blood cells and is involved in vesiculation. Biochim. Biophys. Acta 1763: 330-335, 2006. [PubMed: 16540189] [Full Text: https://doi.org/10.1016/j.bbamcr.2006.02.001]
Meng, Z., Qiu, Y., Lin, K. C., Kumar, A., Placone, J. K., Fang, C., Wang, K.-C., Lu, S., Pan, M., Hong, A. W., Moroishi, T., Luo, M., and 11 others. RAP2 mediates mechanoresponses of the Hippo pathway. Nature 560: 655-660, 2018. [PubMed: 30135582] [Full Text: https://doi.org/10.1038/s41586-018-0444-0]
Ohmstede, C.-A., Farrell, F. X., Reep, B. R., Clemetson, K. J., Lapetina, E. G. RAP2B: a RAS-related GTP-binding protein from platelets. Proc. Nat. Acad. Sci. 87: 6527-6531, 1990. [PubMed: 2118648] [Full Text: https://doi.org/10.1073/pnas.87.17.6527]
Stumpf, A. M. Personal Communication. Baltimore, Md. 04/04/2024.
Torti, M., Ramaschi, G., Sinigaglia, F., Lapetina, E. G., Balduini, C. Association of the low molecular weight GTP-binding protein rap2B with the cytoskeleton during platelet aggregation. Proc. Nat. Acad. Sci. 90: 7553-7557, 1993. [PubMed: 8356055] [Full Text: https://doi.org/10.1073/pnas.90.16.7553]