Alternative titles; symbols
HGNC Approved Gene Symbol: RAP2A
Cytogenetic location: 13q32.1 Genomic coordinates (GRCh38): 13:97,434,169-97,469,128 (from NCBI)
By screening a Raji Burkitt lymphoma cell line cDNA library with Drosophila Dras3 cDNA, Pizon et al. (1988) cloned RAP1A (179520) and RAP2A. The deduced 183-amino acid protein has a calculated molecular mass of 20.7 kD. It contains domains required for GTP binding and a Ras (see 190020)-like C-terminal motif for posttranslational lipid binding and subsequent anchoring to the plasma membrane. Northern blot analysis of lymphocyte mRNA detected transcripts of 2.2, 2.5, and 4.6 kb.
Lerosey et al. (1991) demonstrated that purified recombinant RAP2A bound GTP and exhibited a low intrinsic GTPase activity in the presence of Mg(2+). By site-directed mutagenesis, they showed that gly12 and thr35 were involved in the GTPase activity, thr145 was involved in guanyl nucleotide binding, and ser17 coordinated the Mg(2+) required for GTP binding.
Zhu et al. (2005) stated that Rap2a and Jnk (see MAPK8, 601158), as well as their regulators, are expressed at excitatory synapses in rodent brain, and they identified a functional Rap2a signaling pathway in cultured mouse hippocampal CA1 neurons. Synaptic activity and activation of NR2A (GRIN2A; 138253)-containing NMDA receptor complexes activated Rap2a, which stimulated Jnk activity. Activation of Rap2a and Jnk led to the removal of Glur1 (GRIA1; 138248)- and Glur2 (GRIA2; 138247)-containing AMPA receptor complexes, and was essential for depolarization. In the bidirectional control of synaptic strength, Rap2a activity appeared to complement the long-term depression due to Rap1 (see 179520) signaling and oppose the long-term potentiation due to Ras signaling.
By affinity chromatography of rat brain synaptosome extracts, Kawabe et al. (2010) identified Tnik (610005) among 15 proteins that interacted with immobilized Nedd4 (602278), an E3 ubiquitin ligase. Rap2a coimmunoprecipitated with Nedd4 and Tnik, but only following protein crosslinking. In vitro ubiquitination experiments revealed that Nedd4 monoubiquitinated Rap2a, but not Tnik or any other Ras-related small GTPase examined. Tnik was required for Nedd4 ubiquitination of Rap2a, and Rap2a monoubiquitination blocked Rap2a/Tnik signaling. Nedd4 -/- mouse cortical neurons showed underdeveloped dendrite extensions and arborizations, and expression of dominant-negative Rap2a or Tnik mutants rescued dendrite morphology in Nedd4 -/- embryos. Kawabe et al. (2010) concluded that NEDD4 positively regulates dendrite extension by blocking RAP2A/TNIK signaling.
Meng et al. (2018) identified the Ras-related GTPase RAP2, which is composed of 3 components, RAP2A, RAP2B (179541), 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.
Rousseau-Merck et al. (1990) used cDNA probes to assign 3 RAP genes by in situ hybridization; RAP1A, RAP1B (179530), and RAP2A were assigned to 1p13-p12, 12q14, and 13q34, respectively, without cross-hybridization or any secondary signal.
Kawabe, H., Neeb, A., Dimova, K., Young, S. M., Jr., Takeda, M., Katsurabayashi, S., Mitkovski, M., Malakhova, O. A., Zhang, D.-E., Umikawa, M., Kariya, K., Goebbels, S., Nave, K.-A., Rosenmund, C., Jahn, O., Rhee, J., Brose, N. Regulation of Rap2A by the ubiquitin ligase Nedd4-1 controls neurite development. Neuron 65: 358-372, 2010. [PubMed: 20159449] [Full Text: https://doi.org/10.1016/j.neuron.2010.01.007]
Lerosey, I., Chardin, P., de Gunzburg, J., Tavitian, A. The product of the rap2 gene, member of the ras superfamily: biochemical characterization and site-directed mutagenesis. J. Biol. Chem. 266: 4315-4321, 1991. [PubMed: 1900290]
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]
Pizon, V., Chardin, P., Lerosey, I., Olofsson, B., Tavitian, A. Human cDNAs rap1 and rap2 homologous to the Drosophila gene Dras3 encode proteins closely related to ras in the 'effector' region. Oncogene 3: 201-204, 1988. [PubMed: 3045729]
Rousseau-Merck, M. F., Pizon, V., Tavitian, A., Berger, R. Chromosome mapping of the human RAS-related RAP1A, RAP1B, and RAP2 genes to chromosomes 1p12-p13, 12q14, and 13q34, respectively. Cytogenet. Cell Genet. 53: 2-4, 1990. [PubMed: 2108841] [Full Text: https://doi.org/10.1159/000132883]
Zhu, Y., Pak, D., Qin, Y., McCormack, S. G., Kim, M. J., Baumgart, J. P., Velamoor, V., Auberson, Y. P., Osten, P., van Aelst, L., Sheng, M., Zhu, J. J. Rap2-JNK removes synaptic AMPA receptors during depotentiation. Neuron 46: 905-916, 2005. Note: Erratum: Neuron 47: 321 only, 2005. [PubMed: 15953419] [Full Text: https://doi.org/10.1016/j.neuron.2005.04.037]