Disease relevance of RAP1A

• Using adenovirus, inactivation of Rap1 by expression of rap1GAPII inhibited wound healing [1].
• The endogenous G(alpha)o/i-coupled cannabinoid (CB1) receptor in Neuro-2A cells stimulates the degradation of Rap1GAPII; activation of Rap1 and treatment with pertussis toxin or lactacystin blocks these effects [2].
• Rap1 is variably expressed in whole cell lysates of squamous cell carcinoma (SCC) cell lines [3].
• Furthermore, growth factors induce nuclear translocation of rap1 in oral cancer cells [3].
• Mutation in RAP1 is a rare event in myelodysplastic syndromes [4].

Psychiatry related information on RAP1A

• We have recently reported altered levels of protein kinase A and Rap1 in patients with bipolar disorder [5].
• The cAMP-dependent protein kinase substrate Rap1 in platelets from patients with obsessive compulsive disorder or schizophrenia [6].
• Previous studies have reported that the cAMP-dependent protein kinase and one of its substrates, namely Rap1, are altered in patients with affective disorders [6].

High impact information on RAP1A

• Previously, we showed that tyrosine phosphorylation of p130Cas (Cas) in a cytoskeletal complex is involved in force-dependent activation of the small GTPase Rap1 [7].
• Neither Bqt1 nor Bqt2 alone functions as a connector, but together the two proteins form a bridge between Rap1 (a telomere protein) and Sad1 (an SPB protein) [8].
• Our data suggest the involvement of the RAP1A signal transduction pathway in vasculogenesis or angiogenesis [9].
• Molecular cloning of a GTPase activating protein specific for the Krev-1 protein p21rap1 [10].
• The rap1/Krev-1 gene encodes a ras-related protein that suppresses transformation by ras oncogenes [10].

Chemical compound and disease context of RAP1A

• Finally, a functional role for Rap1 activation was shown by Rap1-induced alpha(v)beta(3) integrin activation and consequent increased melanoma cell migration in vitro [11].
• In this study, we compared levels of Rap1-GTP, Rap1 and tuberin levels in normal brain tissue and 24 grade II-IV astrocytoma specimens [12].
• Expression of human Krev-1 gene in lungs of transgenic mice and subsequent reduction in multiplicity of ethyl carbamate-induced lung adenomas [13].
• Three human prostate cancer cell lines, PC-3, TSU-Pr1, and DU-145 were transfected with a plasmid containing the Krev-1 cDNA and a neomycin resistance gene [14].

Biological context of RAP1A

• Moreover, incubation of similar extracts with the catalytic subunit of cAMP-dependent protein kinase did not cause phosphorylation of RAP2B, as had been observed for the closely homologous proteins, RAP1A and RAP1B [15].
• Requirement for C3G-dependent Rap1 activation for cell adhesion and embryogenesis [16].
• The accelerated cell migration was suppressed by the expression of active Rap1, Rap2 and R-Ras [16].
• LC2 is therefore a biological enhancer of EPAC1 activity toward Rap1 and associated downstream signaling mechanisms [17].
• These findings show that activation of MAP kinase by cAMP requires a SRC family kinase that lies downstream of protein kinase A. A role for RAP1, as documented for the beta(2)-adrenergic receptor, is apparently contingent on receptor endocytosis [18].

Anatomical context of RAP1A

• To carry on our study, we raised stable myogenic cell lines overexpressing wild-type or mutated forms of RAP1A [19].
• Myoblasts overexpressing the GTP-bound mutant did not display specific changes of RAP1A and of late endocytic compartments locations [19].
• In conclusion, C3G-dependent activation of Rap1 is required for adhesion and spreading of embryonic fibroblasts and for the early embryogenesis of the mouse [16].
• Nitric Oxide Produced in Response to Engagement of beta2 Integrins on Human Neutrophils Activates the Monomeric GTPases Rap1 and Rap2 and Promotes Adhesion [20].
• Thus, Epac2 can respond to costimulation by agonists that jointly elevate Ras-GTP and cyclic AMP levels, activating a specific pool of Rap1 at the plasma membrane [21].

Associations of RAP1A with chemical compounds

• Cyclic AMP potentiates vascular endothelial cadherin-mediated cell-cell contact to enhance endothelial barrier function through an Epac-Rap1 signaling pathway [22].
• Furthermore, prostacyclin and forskolin induced cortical actin rearrangement in a Rap1-dependent manner [22].
• Together, these results suggest that JAM1 regulates epithelial cell morphology and beta1 integrin expression by modulating activity of the small GTPase Rap1 [23].
• Also, the activation of Rap1 was blocked by PP1, SU6656, LY294002, GF109203X, or BAPTA-AM, which indicates that the downstream signaling events in Rap1 activation involve Src tyrosine kinases, phosphoinositide 3-kinase, protein kinase C, and release of calcium [20].
• Characterization of GFR, a novel guanine nucleotide exchange factor for Rap1 [24].

Physical interactions of RAP1A

• Krit1 interacted strongly with Krev-1 but only weakly with Ras, suggesting it might specifically regulate Krev-1 activities [25].
• We found that engagement of beta2 integrins on human neutrophils increased the levels of GTP-bound Rap1 and Rap2 [20].
• Stimulation of the G(i)-coupled m2-muscarinic receptor translocates rap1GAPII from the cytosol to the membrane and decreases the amount of GTP-bound Rap1 [26].
• The inactivation of Rap1 was associated with an insulin-stimulated decrease in the amount of Rap1 that was bound to Raf1 [27].
• We have developed a novel assay to monitor the active, GTP-bound form of Rap1 based on the differential affinity of Rap1GTP and Rap1GDP for the Rap binding domain of RalGDS (RBD) [28].

Regulatory relationships of RAP1A

• Thus, we investigated the effect of Rap1 on permeability and the VE-cadherin-mediated cell adhesion by expressing either constitutive active Rap1 or Rap1GAPII [22].
• Epac-1 and -2 (exchange proteins directly activated by cyclic AMP) are guanine-nucleotide exchange factors for the GTPases Rap1 and -2 [21].
• Junctional adhesion molecule 1 regulates epithelial cell morphology through effects on beta1 integrins and Rap1 activity [23].
• However, we identified nitric oxide as the signaling molecule involved in beta2 integrin-induced activation of Rap1 and Rap2 [20].
• Role of Rap1 in promoting sickle red blood cell adhesion to laminin via BCAM/LU [29].

Other interactions of RAP1A

• A novel Epac-specific cAMP analogue demonstrates independent regulation of Rap1 and ERK [30].
• Using a genomic sequence-based positional cloning strategy, we have identified KRIT1, encoding a protein that interacts with the Krev-1/rap1a tumor suppressor, as the CCM1 gene [31].
• Activation of Rap1 resulted in a decrease in permeability and enhancement of VE-cadherin-dependent cell adhesion, whereas inactivation of Rap1 had the counter effect [22].
• However, overexpression of a RAP1 GTPase-activating protein (RAP1GAP), which efficiently clamped cellular RAP1 in the inactive GDP-bound form, did not affect A(2A)-agonist-mediated MAP kinase stimulation [18].
• In CHO-A(2A) cells, the stimulation of the A(2A)-receptor resulted in an activation of RAP1 and formation of RAP1-B-RAF complexes [18].

Analytical, diagnostic and therapeutic context of RAP1A

• Association of Krev-1/rap1a with Krit1, a novel ankyrin repeat-containing protein encoded by a gene mapping to 7q21-22 [25].
• 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 [32].
• Immunoblot analysis of nuclear and cytosolic fractions and immunohistochemistry revealed that in addition to cytoplasmic expression, SCC cells also exhibit prominent punctate rap1 expression in the nucleus [3].
• In epithelial cell cultures, ligation of the extracellular domain of E-cadherin enhances Rap1 activity, which in turn is necessary for the proper targeting of E-cadherin molecules to maturing cell-cell contacts [33].
• This was due to an apparent masking of Rap1 as heat denaturation of the whole cell detergent extracts (5 min at 100 degrees C) resulted in equal immunoprecipitation of Rap1 with this epitope-specific antibody [34].

References