Alternative titles; symbols
HGNC Approved Gene Symbol: RAP1A
Cytogenetic location: 1p13.2 Genomic coordinates (GRCh38): 1:111,542,009-111,716,691 (from NCBI)
Rousseau-Merck et al. (1990) stated that 3 human cDNAs encoding 'new' RAS-related proteins, designated RAP1A, RAP1B (179530), and RAP2 (179540), were isolated by Pizon et al. (1988, 1988). These proteins share approximately 50% amino acid identity with the classical RAS proteins and have numerous structural features in common. The most striking difference between the RAP and RAS proteins resides in their 61st amino acid: glutamine in RAS is replaced by threonine in RAP proteins.
Kitayama et al. (1989) isolated a human cDNA termed Krev1 that can suppress the transformed phenotype of a Kirsten transformed cell line. The predicted amino acid sequence of the Krev1 protein is identical to that of RAP1A.
Boussiotis et al. (1997) noted that C3G (600303) catalyzes GTP exchange of Rap1. Immunoblot analysis showed that in anergic T cells, CBL (165360) is constitutively phosphorylated, CRKL (602007)-C3G complexes are recruited, and Rap1, an antagonist of Ras function and a negative regulator of IL2 transcription, is activated. Boussiotis et al. (1997) suggested that the key determinant of the functional outcome of T cell receptor-initiated signals may be the ratio of Ras-GTP to RAP1-GTP, with the predominance of the former enhancing, and the of the latter blocking, IL2 transcription.
Asha et al. (1999) demonstrated that RAS1-mediated signaling pathways in Drosophila are not influenced by RAP1 levels, suggesting that RAS1 and RAP1 function via distinct pathways. Moreover, a mutation that abolishes the putative cAMP-dependent kinase phosphorylation site of Drosophila RAP1 can still rescue the RAP1 mutant phenotype. Asha et al. (1999) demonstrated that RAP1 is not needed for cell proliferation and cell-fate specification but has a critical function in regulating normal morphogenesis in the eye disc, the ovary, and the embryo. RAP1 mutations also disrupt cell migrations and cause abnormalities in cell shape. These findings indicate a role for RAP proteins as regulators of morphogenesis in vivo.
Mochizuki et al. (2001) used fluorescent resonance energy transfer (FRET)-based sensors to evaluate the spatiotemporal images of growth factor-induced activation of RAS and RAP1. Epidermal growth factor (131530) activated RAS at the peripheral plasma membrane and RAP1 at the intracellular perinuclear region of COS-1 cells. In PC12 cells, nerve growth factor (see 162030)-induced activation of RAS was initiated at the plasma membrane and transmitted to the whole cell body. After 3 hours, high RAS activity was observed at the extending neurites. By using the FRAP (fluorescence recovery after photobleaching) technique, Mochizuki et al. (2001) found that RAS at the neurites turned over rapidly; therefore, the sustained RAS activity at neurites was due to high GTP/GDP exchange rate and/or low GTPase activity, but not to the retention of the active RAS. While previous biochemical analyses rarely detected more than 40% activation of RAS upon growth factor stimulation, Mochizuki et al. (2001) concluded that their data show that growth factor stimulation strongly activates RAS/RAP1 in a very restricted area within cells, and that a large population of RAS or RAP1 remains inactive, causing an apparent low-level response in biochemical assays.
Zhu et al. (2002) examined the small GTPases RAS and RAP in the postsynaptic signaling underlying synaptic plasticity. They showed that RAS relays the NMDA receptor (see 138252) and calcium/calmodulin-dependent protein kinase II (see 114078) signaling that drives synaptic delivery of AMPA receptors (see 138248) during long-term potentiation. In contrast, RAP was found to mediate the NMDA receptor-dependent removal of synaptic AMPA receptors that occurs during long-term depression. The authors determined that RAS and RAP exert their effects on AMPA receptors that contain different subunit composition. Thus, RAS and RAP, whose activities can be controlled by postsynaptic enzymes, serve as independent regulators for potentiating and depressing central synapses.
Knox and Brown (2002) found that even distribution of adherens junctions is an active process that requires RAP1. Cells mutant for RAP1 condensed their adherens junctions to 1 side of the cell. This disrupted normal epithelial cell behavior and mutant cell clones dispersed into the surrounding wildtype tissue. RAP1 is enriched at adherens junctions, particularly between newly divided sister cells where it may reseal the adherens junction ring.
Rousseau-Merck et al. (1990) used cDNA probes to assign the RAP genes by in situ hybridization; RAP1A, RAP1B, and RAP2A were assigned to 1p13-p12, 12q14, and 13q34, respectively, without cross-hybridization or any secondary signal. By fluorescence in situ hybridization, Takai et al. (1993) narrowed the assignment of the KREV1 gene to 1p13.3 and mapped its pseudogene (KREV1P) to 14q24.3.
Associations Pending Confirmation
In a boy, born of unrelated Turkish parents, with features reminiscent of Kabuki syndrome (147920), Bogershausen et al. (2015) identified a c.488G-C transversion (c.488G-C, NM_001010935.2) in the RAP1A gene, resulting in an arg163-to-thr (R163T) substitution at a conserved residue in the GTPase domain. The variant, which was found by trio-based whole-exome sequencing, was found in heterozygous state in the unaffected father, but not in the mother. The mutation was homozygous in the patient due to paternal uniparental isodisomy (UPD) for chromosome 1. The RAP1A missense variant was located within a 12-Mb duplication of chromosome 1p13.1-p22.1 that had previously been identified in a patient with Kabuki-like syndrome by Lo et al. (1998). The R163T variant was not found in public databases, including the 1000 Genomes Project, Exome Variant Server, and ExAC. In vitro studies showed a reduction of active GTP-bound RAP1A after stimulation of cells with EGF, suggesting a loss-of-function effect. Expression of the R163T variant was unable to rescue convergent-extension (CE) defects in rap1a-null zebrafish, also suggesting that it is a loss-of-function allele. RAP1A R163T patient fibroblasts showed disorganization of the actin cytoskeleton and attenuated MEK/ERK signaling. The patient had growth defects with short stature and microcephaly, developmental delay, seizures, joint hyperlaxity, short neck, Sprengel deformity, and dysmorphic facial features, including wide and long palpebral fissures, eversion of the lateral lower eyelids, arched eyebrows, long dense eyelashes, flat midface, dysplastic ears, and strabismus.
Using mice transgenic for constitutive expression of Rap1a within the T-cell lineage, Sebzda et al. (2002) found that instead of anergy, these T cells showed enhanced T-cell receptor-mediated responses, both in thymocytes and in mature T cells. In addition, Rap1a activation induced strong activation of beta-1 (135630) and beta-2 (600065) integrins. The authors concluded that Rap1a positively influences T cells by augmenting their responses and directing integrin activation.
Li et al. (2007) generated mice lacking Rap1a. Although loss of Rap1a did not initially affect mouse size or viability, upon backcross into C57BL/6J mice some Rap1a -/- embryos died in utero. Rap1a -/- mice showed no defects in development of T, B, or myeloid cells. However, Rap1a -/- macrophages exhibited increased random movement, or haptotaxis, on fibronectin (FN1; 135600) and vitronectin (VTN; 193190) matrices that correlated with decreased adhesion. The chemotactic responses of Rap1a -/- lymphoid and myeloid cells to Cxcl12 (600835) and Ccl21 (602737) were significantly reduced, but FcR (see 146790)-mediated phagocytosis increased. Neutrophils from Rap1a -/- mice had reduced superoxide production when stimulated with the synthetic chemotactic peptide FMLP. Li et al. (2007) concluded that, in spite of 95% sequence identity, similar intracellular distribution, and broad tissue distribution, Rap1a and Rap1b are not functionally redundant and, instead, differentially regulate some cellular events.
Bogershausen et al. (2015) found that morpholino knockdown of rap1a, rap1b (179530), kmt2d (602113), and kdm6a (300128) in zebrafish resulted in similar convergent-extension defects (CE defects), including short thin embryos with shorter anterior-posterior axis, wider notochord, and poorly developed head, eye, and tail structures. Mutant zebrafish also showed cartilaginous jaw defects associated with abnormal organization of chondrocytes and abnormal actin dynamics and cell intercalation. The phenotypes were rescued by expression of wildtype human RAP1A, but not by RAP1A R163T mutant, suggesting the relevance of the genes in causing the phenotype and the existence of a direct biochemical relationship among the genes. The phenotypes could also be rescued in zebrafish by rebalancing MEK/ERK signaling via administration of small molecule inhibitors of MEK.
Stefanini et al. (2018) found that mice with megakaryocyte-specific Rap1a and Rap1b double-knockout were viable, fertile, and healthy, with no spontaneous bleeding, but that they developed macrothrombocytopenia. Loss of Rap1a and Rap1b led to 80 to 90% inhibition of integrin activation. The lack of complete platelet integrin activation in the absence of Rap1a and Rap1b was due to limited integrin activation mediated by Talin1 (186745), but not by other Rap proteins, such as Rap2 GTPases, also expressed in platelets. Further analysis showed that Rap isoforms had redundant and isoform-specific functions in platelets and were important for platelet spreading, clot contraction, release of second-wave mediators, platelet adhesion, and formation of thrombotic and hemostatic plugs. However, Rap1 signaling in platelets was dispensable for vascular integrity during development and at sites of inflammation.
Asha, H., de Ruiter, N. D., Wang, M.-G., Hariharan, I. K. The Rap1 GTPase functions as a regulator of morphogenesis in vivo. EMBO J. 18: 605-615, 1999. [PubMed: 9927420] [Full Text: https://doi.org/10.1093/emboj/18.3.605]
Bogershausen, N., Tsai, I. C., Pohl, E., Kiper, P. O., Beleggia, F., Percin, E. F., Keupp, K., Matchan, A., Milz, E., Alanay, Y., Kayserili, H., Liu, Y., and 16 others. RAP1-mediated MEK/ERK pathway defects in Kabuki syndrome. J. Clin. Invest. 125: 3585-3599, 2015. [PubMed: 26280580] [Full Text: https://doi.org/10.1172/JCI80102]
Boussiotis, V. A., Freeman, G. J., Berezovskaya, A., Barber, D. L., Nadler, L. M. Maintenance of human T cell anergy: blocking of IL-2 gene transcription by activated Rap1. Science 278: 124-128, 1997. [PubMed: 9311917] [Full Text: https://doi.org/10.1126/science.278.5335.124]
Kitayama, H., Sugimoto, Y., Matsuzaki, T., Ikawa, Y., Noda, M. A ras-related gene with transformation suppressor activity. Cell 56: 77-84, 1989. [PubMed: 2642744] [Full Text: https://doi.org/10.1016/0092-8674(89)90985-9]
Knox, A. L., Brown, N. H. Rap1 GTPase regulation of adherens junction positioning and cell adhesion. Science 295: 1285-1288, 2002. [PubMed: 11847339] [Full Text: https://doi.org/10.1126/science.1067549]
Li, Y., Yan, J., De, P., Chang, H.-C., Yamauchi, A., Christopherson, K. W., II, Paranavitana, N. C., Peng, X., Kim, C., Munugalavadla, V., Kapur, R., Chen, H., Shou, W., Stone, J. C., Kaplan, M. H., Dinauer, M. C., Durden, D. L., Quilliam, L. A. Rap1a null mice have altered myeloid cell functions suggesting distinct roles for the closely related Rap1a and 1b proteins. J. Immun. 179: 8322-8331, 2007. Note: Erratum: J. Immun. 180: 3612 only, 2008. [PubMed: 18056377] [Full Text: https://doi.org/10.4049/jimmunol.179.12.8322]
Lo, I. F. M., Cheung, L. Y. K., Ng, A. Y. Y., Lam, S. T. S. Interstitial dup(1p) with findings of Kabuki make-up syndrome. Am. J. Med. Genet. 78: 55-57, 1998. [PubMed: 9637424]
Mochizuki, N., Yamashita, S., Kurokawa, K., Ohba, Y., Nagai, T., Miyawaki, A., Matsuda, M. Spatio-temporal images of growth-factor-induced activation of Ras and Rap1. Nature 411: 1065-1068, 2001. [PubMed: 11429608] [Full Text: https://doi.org/10.1038/35082594]
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]
Pizon, V., Lerosey, I., Chardin, P., Tavitian, A. Nucleotide sequence of a human cDNA encoding ras-related protein (rap1B). Nucleic Acids Res. 16: 7719 only, 1988. [PubMed: 3137530] [Full Text: https://doi.org/10.1093/nar/16.15.7719]
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]
Sebzda, E., Bracke, M., Tugal, T., Hogg, N., Cantrell, D. A. Rap1a positively regulates T cells via integrin activation rather than inhibiting lymphocyte signaling. Nature Immun. 3: 251-258, 2002. [PubMed: 11836528] [Full Text: https://doi.org/10.1038/ni765]
Stefanini, L., Lee, R. H., Paul, D. S., O'Shaughnessy, E. C., Ghalloussi, D., Jones, C. I., Boulaftali, Y., Poe, K. O., Piatt, R., Kechele, D. O., Caron, K. M., Hahn, K. M., Gibbins, J. M., Bergmeier, W. Functional redundancy between RAP1 isoforms in murine platelet production and function. Blood 132: 1951-1962, 2018. [PubMed: 30131434] [Full Text: https://doi.org/10.1182/blood-2018-03-838714]
Takai, S., Nishino, N., Kitayama, H., Ikawa, Y., Noda, M. Mapping of the KREV1 transformation suppressor gene and its pseudogene (KREV1P) to human chromosome 1p13.3 and 14q24.3, respectively, by fluorescence in situ hybridization. Cytogenet. Cell Genet. 63: 59-61, 1993. [PubMed: 8449039] [Full Text: https://doi.org/10.1159/000133503]
Zhu, J. J., Qin, Y., Zhao, M., Van Aelst, L., Malinow, R. Ras and Rap control AMPA receptor trafficking during synaptic plasticity. Cell 110: 443-455, 2002. [PubMed: 12202034] [Full Text: https://doi.org/10.1016/s0092-8674(02)00897-8]