Disease relevance of RASA1

• RASA1 gene-disease database  
• RASA1: variable phenotype with capillary and arteriovenous malformations [1].
• A conserved alternative splice in the von Recklinghausen neurofibromatosis (NF1) gene produces two neurofibromin isoforms, both of which have GTPase-activating protein activity [2].
• The p210bcr/abl tyrosine kinase appears to be responsible for initiating and maintaining the leukemic phenotype in chronic myelogenous leukemia (CML) patients. p21ras-p120GAP interactions play a central role in transducing mitogenic signals [3].
• Negative regulation of p120GAP GTPase promoting activity by p210bcr/abl: implication for RAS-dependent Philadelphia chromosome positive cell growth [3].
• Ribosylation of Val14rho with the ADP-ribosyltransferase C3 from clostridium botulinum, before microinjection, renders the protein biologically inactive, but it has no effect on either its intrinsic biochemical properties or on its interaction with the GTPase activating protein, rho GAP [4].

Psychiatry related information on RASA1

• A recent study using this approach has identified new proteins and interactions that might be involved in the pathogenesis of the neurodegenerative disorder Huntington's disease, including a GTPase-activating protein that co-localizes with protein aggregates in Huntington's disease patients [5].
• The WAVE-associated GTPase activating protein called WRP is implicated in human mental retardation, and WAVE-1 knock-out mice have altered behavior [6].

High impact information on RASA1

• GTPase activating protein (GAP), phosphatidylinositol 3-kinase (PI3-k) and microtubule associate protein kinase (MAPk2) [7].
• A GTPase-activating protein probably binds to and stabilizes the conformation of its cognate G protein that recognizes the transition state for hydrolysis, and may insert a catalytic residue into the G protein active site [8].
• TSC2 inhibits cell growth by acting as a GTPase-activating protein toward Rheb, thereby inhibiting mTOR, a central controller of cell growth [9].
• In this issue of Cell, provide intriguing evidence for a new pathway that links polarity proteins and vesicle transport to the maintenance of tight junctions, through the control of Cdc42 by Rich1, a GTPase-activating protein [10].
• Finally, we identified RASAL1, a RAS-GTPase-activating protein, as a transcription target through which PITX1 affects RAS function [11].

Chemical compound and disease context of RASA1

• In normal cells, tuberin having GTPase-activating protein properties toward Rheb controls signals of nutrient depletion, hypoxia, or stress, not allowing activation of mTOR and subsequent protein translation and cell proliferation [12].
• 3. Inhibition of Gi activity by either pertussis toxin or the GTPase activating protein RGS16 abolished inhibitory as well as stimulatory effects of clonidine on Iout [13].

Biological context of RASA1

• Lack of RASA1 activity caused inhibition of cell motility, possibly through p190-RhoGAP [1].
• PDGF induction of tyrosine phosphorylation of GTPase activating protein [14].
• The carboxy-terminal catalytic domain of the GTPase-activating protein inhibits nuclear signal transduction and morphological transformation mediated by the CSF-1 receptor [15].
• Murine Rasa1 knockout and tetraploid-aggregated embryos with RNA interference exhibited abnormal vascular development [1].
• The binding of cytoplasmic signaling proteins such as phospholipase C-gamma 1 and Ras GTPase-activating protein to autophosphorylated growth factor receptors is directed by their noncatalytic Src homology region 2 (SH2) domains [16].

Anatomical context of RASA1

• In fibroblasts, CSF-1 stimulation also induced the phosphorylation of the GTPase-activating protein (GAP)-associated protein p62 on tyrosine, although GAP itself was a relatively poor substrate [17].
• Morphological transformation of NIH 3T3 cells was observed following coexpression of a portion of the ras GTPase-activating protein (GAP) comprising the amino terminus (GAP-N) and a mutant of v-src (MDSRC) lacking the membrane-localizing sequence [18].
• In addition, we demonstrate that TCR activation of normal CD4+ T cells induced the formation of p120GAP and PLCgamma1-containing complexes [19].
• Since p85 is known to interact with GTPase-activating protein in 3T3-L1 adipocytes, the overexpressed p85N-SH2 peptide could titrate out cellular GTPase-activating protein by direct association, such that it is unavailable to hydrolyze GTP-bound Ras [20].
• These findings demonstrate an important role for annexin A6 in regulating plasma membrane localization of p120GAP and hence Ras activity [21].

Associations of RASA1 with chemical compounds

• These guanine nucleotide-binding Ras proteins specifically interact with a cellular GTPase-activating protein (GAP) [14].
• Like other small GTP-binding proteins, CDC42 is activated by a guanosine exchange factor and inactivated by a GTPase-activating protein (GAP) [22].
• The importance of two conserved arginine residues for catalysis by the ras GTPase-activating protein, neurofibromin [23].
• Mapping the site of interaction between annexin VI and the p120GAP C2 domain [24].
• Glycine-12 in the transition state mimic is within van der Waals distance of both arginine-789 of GAP-334 and glutamine-61 of Ras, and even its mutation to alanine would disturb the arrangements of residues in the transition state [25].
• Fibronectin-integrin-mediated FAK activation and phosphorylation promote SH2-mediated binding of p120RasGAP to FAK and FAK-mediated p190A tyrosine phosphorylation [26].

Physical interactions of RASA1

• In vitro binding studies indicate that SH3 domains of Grb2 or RasGAP are required for their binding to huntingtin [27].
• In contrast, insulin activation does not displace PDGF receptors from binding sites on Ras GTPase-activating protein [28].
• Insulin receptor-mediated p62dok tyrosine phosphorylation at residues 362 and 398 plays distinct roles for binding GTPase-activating protein and Nck and is essential for inhibiting insulin-stimulated activation of Ras and Akt [29].
• Upregulation of the RAS-GTPase activating protein (GAP)-binding protein (G3BP) in proliferating RPE cells [30].
• The GTPase activating protein (ras-GAP) has been shown to interact with p21ras at a domain defined by amino acids 32-40 [31].

Enzymatic interactions of RASA1

• Our results obtained with homogeneous protein preparations show that the activated epidermal growth factor (EGF) receptor phosphorylates p120-GAP at one site [32].
• By using an antiserum against the GTPase-activating protein, we found that p120GAP is rapidly phosphorylated in tyrosine in response to erythropoietin [33].

Co-localisations of RASA1

• Here we show that G3BP colocalizes and physically interacts with RasGAP at the plasma membrane of serum-stimulated but not quiescent Chinese hamster lung fibroblasts [34].

Regulatory relationships of RASA1

• The GTPase-activating protein of Ras suppresses platelet-derived growth factor beta receptor signaling by silencing phospholipase C-gamma 1 [35].
• Finally, we demonstrated that annexin A6 promotes plasma membrane targeting of p120GAP in A431 cells in response to a variety of stimuli, resulting in colocalization with H-Ras [21].
• These oncogenes, which are frequently expressed in human malignancies, code for proteins (p21ras) that are locked in the activated GTP-bound state because their GTPase is refractory to the ras-specific GTPase activating protein (GAP) [36].
• EGF stimulates RasGAP protein synthesis and does not affect its degradation rate [37].
• In addition, the exogenous expression of the NF1-GTPase-activating protein-related domain suppressed the NF1 siRNA-induced phenotypes [38].

Other interactions of RASA1

• When expressed in non-mammalian systems, the region of the NF1 gene homologous to p120GAP produces a protein with GAP-like activity [39].
• Thus, IQGAP1 appears to represent a novel RasGAP-like protein that may link Ras signaling to some calmodulin-mediated process [40].
• Tyr(P)992 receptors were associated with more SOS, Ras-GTPase activating protein, phosphatidylinositol 3-kinase, and SHPTP2/syp, but less Grb2, than receptors in the general population, and these receptors were more heavily phosphorylated than the general population of active receptors [41].
• Annexin A6 is a calcium-dependent membrane-binding protein that interacts with signalling proteins, including the GTPase-activating protein p120GAP, one of the most important inactivators of Ras [21].
• However, elevated Ras-GTP levels were not the result of oncogenic Ras mutations, altered p120-GAP function, growth factor receptor activation, or abnormal p53, Rb, or p16 expression [42].

Analytical, diagnostic and therapeutic context of RASA1

• Purification, characterization, and western blot analysis of human GTPase-activating protein from native and recombinant sources [43].
• In contrast to the signaling triggered by surface Ig engagement in B lymphocytes, CD38 ligation did not appear to induce tyrosine phosphorylation of the src-like protein tyrosine kinases lyn, fyn, and btk, or of vav- and ras-GTPase-activating protein, nor did it induce detectable changes in cytosolic CA2+ concentrations [44].
• Molecular cloning of a GTPase activating protein specific for the Krev-1 protein p21rap1 [45].
• Hematopoietic progenitors isolated from CML patients in the chronic phase contain a constitutively tyrosine-phosphorylated protein that migrates at 62 kDa by SDS-PAGE and associates with the p120 ras GTPase-activating protein (GAP) [46].
• These data indicate that p120 GAP is involved in human normal and leukemic hemopoiesis and strongly suggest that GAP is not only a p21ras inhibitor (signal terminator), but also a positive signal transducer [47].

References