Rho guanine nucleotide exchange factor 7 is a protein that in humans is encoded by the ARHGEF7 gene.
ARHGEF7 is commonly known as the <u>p</u>21-<u>a</u>ctivated protein kinase e<u>x</u>change factor beta (beta-PIX or òPIX), because it was identified by binding to p21-activated kinase (PAK) and also contains a guanine nucleotide exchange factor domain.
òPIX is a multidomain protein that functions both as a signaling scaffold protein and as an enzyme. òPIX shares this domain structure and signaling function with the highly similar ARHGEF6/ñPIX protein.
òPIX undergoes extensive alternative splicing to generate multiple variant proteins containing or lacking particular protein domains. Adult forms all lack the amino terminal CH domain, and the two major adult variants have alternate carboxyl terminal region (termed ò1 and ò2): ò1 forms contain the coiled-coil trimerization domain and the PDZ-target motif for binding to PDZ proteins (see below), while ò2 forms lack both domains and their corresponding functions.
òPIX contains a central DH/PH RhoGEF domain that functions as a guanine nucleotide exchange factor (GEF) for small GTPases of the Rho family, and specifically Rac and Cdc42. Like other GEFs, òPIX can promote both release of GDP from an inactive small GTP-binding protein and binding of GTP to promote its activation. Signaling scaffolds bind to specific partners to promote efficient signal transduction by arranging sequential elements of a pathway near each other to facilitate interaction/information transfer, and also by holding these partner protein complexes in specific locations within the cell to promote local or regional signaling. In the case of òPIX, its SH3 domain binds to partner proteins with appropriate polyproline motifs, and particularly to group I p21-activated kinases (PAKs) (PAK1, PAK2 and PAK3). PAK is bound to the òPIX SH3 domain in the inactive state, and activated Rac1 or Cdc42 binding to this PAK stimulates its protein kinase activity leading to downstream target protein phosphorylation; since òPIX can activate the "p21" small GTPases Rac1 or Cdc42 through its GEF activity, this òPIX/PAK/Rac complex exemplifies a scaffolding function.
Structurally, òPIX assembles as a trimer through a carboxyl-terminal coiled-coil domain that is present in the major carboxyl terminal splice variant ò1, and further interacts with dimers of GIT1 or GIT2 through a nearby GIT-binding domain to form oligomeric GIT-PIX complexes. Through this GIT-PIX complex, the scaffolding function of òPIX is amplified by also being able to hold GIT partners in proximity to òPIX partners. In contrast, ò2 carboxyl terminal variants lack this coiled-coil region and are predicted to be unable to trimerize. The major carboxyl terminal variant ò1 also has a PDZ domain binding target motif that binds to the PDZ domains in SHANK1, scribble, and SNX27 proteins. Some splice variants of òPIX contain an amino-terminal Calponin Homology (CH) domain whose functions remain relatively poorly defined, but may interacts with parvin/affixin family proteins. òPIX variants with this extended amino terminal CH domain are most highly expressed early in development, but appear rare after birth.
òPIX has been reported to interact with over 120 proteins.
Major interacting proteins include: