p190RhoGAPs, the ARHGAP35- and ARHGAP5-Encoded Proteins, in Health and Disease

Abstract

Small guanosine triphosphatases (GTPases) gathered in the Rat sarcoma (Ras) superfamily represent a large family of proteins involved in several key cellular mechanisms. Within the Ras superfamily, the Ras homolog (Rho) family is specialized in the regulation of actin cytoskeleton-based mechanisms. These proteins switch between an active and an inactive state, resulting in subsequent inhibiting or activating downstream signals, leading finally to regulation of actin-based processes. The On/Off status of Rho GTPases implicates two subsets of regulators: GEFs (guanine nucleotide exchange factors), which favor the active GTP (guanosine triphosphate) status of the GTPase and GAPs (GTPase activating proteins), which inhibit the GTPase by enhancing the GTP hydrolysis. In humans, the 20 identified Rho GTPases are regulated by over 70 GAP proteins suggesting a complex, but well-defined, spatio-temporal implication of these GAPs. Among the quite large number of RhoGAPs, we focus on p190RhoGAP, which is known as the main negative regulator of RhoA, but not exclusively. Two isoforms, p190A and p190B, are encoded by ARHGAP35 and ARHGAP5 genes, respectively. We describe here the function of each of these isoforms in physiological processes and sum up findings on their role in pathological conditions such as neurological disorders and cancers.

Keywords: GTPase-activating proteins; GTPases; RhoA; actin; acto-myosin; cancers; neurological diseases.

Figure 1

Structure of p190RhoGAP. The structural organization of p190RhoGAP is represented (structural view) and the corresponding function of each domain is indicated when determined (functional view). From its N-terminus, p190RhoGAP is composed of a guanosine triphosphate (GTP)-binding domain (GBD) (13–249) and four FF domains (FF) (251–533) that can bind TFII-I, eIF3A, or Rac1 proteins. In the middle domain, two pseudoGTPase domains, pG1 (592–767) and pG2 (766–958) have been identified. The protrusion localization sequence (PLS) (380–971) is implicated in the localization and the regulation of the function of p190A. A polybasic region (PBR) (1213–1236), mainly composed of basic amino acids, binds to acidic phospholipids. The GTPase activating proteins (GAP) domain (1259–1513) is located at the C-terminus end of the protein and is responsible for the GAP catalytic function of p190A and p190B. Identified residues involved in the function of p190RhoGAP are indicated on the figure (number of amino acids corresponds to the rat p190A protein sequence). For the functional view, bold indicates data obtained for both p190A and p190B. Italic indicates data obtained only for p190B, whereas basic font indicates data obtained for p190A.

Figure 2

P190A and p190B partners. Co-IP: Co-immunoprecipitation; ND: Not Determined.

Figure 2

P190A and p190B partners. Co-IP: Co-immunoprecipitation; ND: Not Determined.

Figure 3

Cellular functions of p190A. P190A functions occurring independently of small GTPases are indicated in orange and those implicating the small GTPases are indicated in blue.