Disease relevance of ARHGAP1

• We report here the identification of a novel member of BNIPL family, designated Bcl-2/adenovirus E1B 19kDa interacting protein 2 like-2 (BNIPL-2), which interacts with Bcl-2 and Cdc42GAP [1].
• ExoS is a bifunctional Type III cytotoxin of Pseudomonas aeruginosa with N-terminal Rho GTPase-activating protein (RhoGAP) and C-terminal ADP-ribosyltransferase domains [2].
• Herein, we describe the identification, characterization and mutational analysis of a novel RHOGAP designated as ARHGAP8, which is located within a critical region of loss-of-heterozygosity on chromosome 22q13.31 in breast and colorectal carcinomas [3].
• We have previously observed the absence of RhoGAP transcript in a breast tumor specimen [4].
• Rho GTPase-activating protein deleted in liver cancer suppresses cell proliferation and invasion in hepatocellular carcinoma [5].

Psychiatry related information on ARHGAP1

• A recently identified gene in Xq12, encoding a Rho-GTPase-activating protein, was found to be mutated in individuals with mental retardation [6].
• Induction of RhoGAP and pathological changes characteristic of Alzheimer's disease by UAHFEMF discharge in rat brain [7].

High impact information on ARHGAP1

• RhoGAP also appears to function by stabilizing several regions of RhoA that are important in signalling the hydrolysis of GTP [8].
• The Rho GAP activity mediated cell rounding and loss of stress fibers when ARAP1 was overexpressed [9].
• In contrast to RasGAP and RhoGAP, Arg-74 could be substituted by lysine and contributed significantly to the binding of Ran [10].
• Therefore, we suggest a GAP mechanism for rna1p, which constitutes a variation of the arginine finger mechanism found for Ras GAP and RhoGAP [10].
• Here, we identify ARHGAP10--a novel Rho GTPase-activating protein (Rho-GAP) that is recruited to Golgi membranes through binding to GTP-ARF1 [11].

Chemical compound and disease context of ARHGAP1

• Study of two families containing individuals with nephrogenic diabetes insipidus (NDI) indicated different types of 21.3 kb and 26.3 kb deletions involving the AVPR2 and ARHGAP4 (RhoGAP C1) genes [12].

Biological context of ARHGAP1

• Tyrosine phosphorylation of the Bcl-2-associated protein BNIP-2 by fibroblast growth factor receptor-1 prevents its binding to Cdc42GAP and Cdc42 [13].
• Cdc42, a member of the Rho family of GTP-binding proteins, has been implicated in a variety of biological activities, including the organization of the actin cytoskeleton, changes in cell morphology and motility, intracellular trafficking, cell cycle progression, and cellular transformation [14].
• BNIPL-2, a novel homologue of BNIP-2, interacts with Bcl-2 and Cdc42GAP in apoptosis [1].
• Here we have compared the kinetics of interaction between recombinant RhoA and the RhoGAP domains of p190, p50RhoGAP, Bcr, and 3BP-1 [15].
• Transfection of RhoGAP into MCF7 cells significantly inhibited cell growth [4].

Anatomical context of ARHGAP1

• NIH3T3 cells overexpressing RhoGAP showed considerable inhibition of stress fiber formation [4].
• The RhoGAP transcript is truncated in some breast carcinoma cell lines and it has low expression in other breast cancer cell lines as compared to a normal breast cell line [4].
• Podosome-like structures present at the leading edge in wild-type neutrophils were significantly reduced in CDC42GAP(-/-) cells [16].
• Similar morphological changes were observed in HtTA-1 HeLa cells expressing just the myr 5 Rho-GAP domain but not in cells expressing myr 5 M1695 [17].
• These results suggest that p200RhoGAP is involved in the regulation of neurite outgrowth by exerting its RhoGAP activity and that its cellular activity may be regulated through interaction with Src-like tyrosine kinases [18].

Associations of ARHGAP1 with chemical compounds

• This argues that the introduction of the arginine finger is insufficient for GAP activity and that the GAP must fulfill an additional function, one possibility being the engagement and stabilization of the conformationally sensitive switch regions of Cdc42 [14].
• ExoS Rho GTPase-activating protein activity stimulates reorganization of the actin cytoskeleton through Rho GTPase guanine nucleotide disassociation inhibitor [2].
• The results suggest that GEF facilitates nucleotide exchange by destabilizing both bound nucleotide and Mg(2+), whereas RhoGAP utilizes the Mg(2+) cofactor to achieve high catalytic efficiency and specificity [19].
• Using glutathione S-transferase recombinant proteins, immunoprecipitation studies, and yeast two-hybrid assays, it was found that BNIP-2 and Cdc42GAP could form homo and hetero complexes via their conserved BCH domains [20].
• It consists of an N-terminal RhoGAP domain and a C-terminal proline-rich region [21].

Physical interactions of ARHGAP1

• Cells expressing the BNIP-2 mutants devoid of this motif or/and the 34-amino acids immediately upstream to this sequence failed to elicit cell elongation and membrane protrusions despite that the protein still remained in the cytoplasm and interacted with Cdc42GAP [22].
• These results provide the first evidence that a RhoGAP functionally interacts with cortactin and represents a novel determinant in the regulation of cell dynamics [23].
• In addition, we have replaced the conserved arginine (Arg305), which was suggested by structural studies to be a key catalytic residue, with an alanine and found that the R305A Cdc42-GAP mutant has a greatly diminished catalytic capacity but is still able to bind Cdc42 with high affinity [24].

Regulatory relationships of ARHGAP1

• The complex of a heterotrimeric G protein with its activating protein shows that the latter protein does not participate directly in the hydrolytic reaction and has a different structure of RhoGAP and RasGAP [25].
• Tyrosine phosphorylation of p250GAP by Fyn would regulate its RhoGAP activity, subcellular localization, or interactions with other proteins, leading to morphological and phenotypic changes of oligodendrocytes [26].
• Furthermore, we found that GTP hydrolysis by TC10 in the vicinity of the plasma membrane was dependent on Rac and the redox-regulated Rho GAP, p190RhoGAP-A [27].
• Aurora B kinase is known to regulate localization of centralspindlin and may regulate the activity of the RhoGAP component of centralspindlin [28].
• Taken together, these results suggest that ET-1 induces Rho-kinase activation and subsequent phosphorylation of p190A RhoGAP, leading to prolonged RhoA activation [29].

Other interactions of ARHGAP1

• Thus, CDC42GAP may function as a link between CDC42 and other signaling pathways [30].
• Deletion experiments indicated that the BCH domain of BNIPL-2 is critical for its interactions with the Bcl-2 and Cdc42GAP and also for its cell death-inducing function [1].
• ARHGAP27 and ARHGAP12 shared the common-domain structure, consisting of SH3, WW, PH, and RhoGAP domains [31].
• Our findings provide evidence that cell morphology changes and migration are coordinated via multiple domains in BPGAP1 and present a novel mode of regulation for cell dynamics by a RhoGAP protein [32].
• However, the 85 kDa regulatory subunit (p85) of the phosphoinositide 3-kinase (PI-3K) is homologous with the Cdc42GAP and contains the essential arginine residue, but is ineffective as a GAP [14].

Analytical, diagnostic and therapeutic context of ARHGAP1

• We have used site-specific mutagenesis to elucidate the limit domain for GAP activity in Cdc42-GAP, and show that in addition to the known GAP-homology domain (three conserved boxes), a C-terminal region outside that domain is also essential for GAP activity [24].
• Electroporation of anti-pp60c-src antibody into cultured, adherent smooth muscle cells blocked the angiotensin II stimulation of Ras-GAP and Rho-GAP tyrosine phosphorylation [33].
• Sequence analysis shows that XrGAP protein shares 60% overall amino acids identity with a human Rho-GTPase activating protein (ARHGAP10) that is highly expressed in the brain [34].

References