Biology:ARHGEF6

Short description: Protein-coding gene in the species Homo sapiens

Generic protein structure example

Rho guanine nucleotide exchange factor 6 is a protein that, in humans, is encoded by the ARHGEF6 gene.

ARHGEF6 is commonly known as the p21-activated protein kinase exchange factor alpha (alpha-PIX or αPIX), because it was identified by binding to p21-activated kinase (PAK) and also contains a guanine nucleotide exchange factor domain.

Domains and functions

αPIX is a multidomain protein that functions both as a signaling scaffold protein and as an enzyme. αPIX shares this domain structure and signaling function with the highly similar ARHGEF7/βPIX protein. αPIX 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, αPIX 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 αPIX, 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 αPIX 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 αPIX can activate the “p21’’ small GTPases Rac1 or Cdc42 through its GEF activity, this αPIX/PAK/Rac complex exemplifies a scaffolding function. Structurally, αPIX assembles as a trimer through its carboxyl-terminal coiled-coil domain, 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 αPIX is amplified by also being able to hold GIT partners in proximity to αPIX partners. αPIX contains an amino-terminal Calponin Homology (CH) domain whose functions remain relatively poorly defined, but interacts with parvin/affixin family proteins.

Because the ARHGEF6 gene is located on the X chromosome so that males have only one copy, mutations in this gene in humans can cause X-chromosome-linked non-specific intellectual disability, as can mutations affecting its binding partner PAK3 whose gene is also located on the X chromosome. In animal models, loss of ARHGEF6 gene function is associated with neuronal synapse defects, immune T-cell migration and maturation defects, and hearing loss.

Interactions

αPIX has been reported to interact with over 40 proteins.

Major interacting proteins include:

• Itself, or the highly-related ARHGEF7/βPIX via a trimeric coiled-coil interaction.
• GIT1 or GIT2 dimers via GIT-binding domain.
• p21-activated kinases (PAKs) 1, 2 and 3 via SH3 domain.
• c-Cbl via SH3 domain.
• Rho family GTP-binding protein family members Rac1 and Cdc42, activated via DHPH RhoGEF domain.

See also

• Rho family of GTPases
• Scaffold protein
• Guanine nucleotide exchange factor
• X-linked intellectual disability

External links

• Human ARHGEF6 genome location and ARHGEF6 gene details page in the UCSC Genome Browser.
• Overview of all the structural information available in the PDB for UniProt: Q15052 (Human Rho guanine nucleotide exchange factor 6) at the PDBe-KB.
• Overview of all the structural information available in the PDB for UniProt: Q8K4I3 (Mouse Rho guanine nucleotide exchange factor 6) at the PDBe-KB.

Further reading

• "Localisation of a gene for non-specific X linked mental retardation (MRX46) to Xq25-q26". J. Med. Genet. 35 (10): 801–5. 1999. doi:10.1136/jmg.35.10.801. PMID 9783701. 
• "alphaPIX nucleotide exchange factor is activated by interaction with phosphatidylinositol 3-kinase". Oncogene 18 (41): 5680–90. 1999. doi:10.1038/sj.onc.1202936. PMID 10523848. 
• "Activation of the PAK-related kinase by human immunodeficiency virus type 1 Nef in primary human peripheral blood lymphocytes and macrophages leads to phosphorylation of a PIX-p95 complex". J. Virol. 73 (12): 9899–907. 1999. doi:10.1128/JVI.73.12.9899-9907.1999. PMID 10559302. 
• "The GIT family of ADP-ribosylation factor GTPase-activating proteins. Functional diversity of GIT2 through alternative splicing". J. Biol. Chem. 275 (29): 22373–80. 2000. doi:10.1074/jbc.275.29.22373. PMID 10896954. 
• "Characterization of ARHGEF6, a guanine nucleotide exchange factor for Rho GTPases and a candidate gene for X-linked mental retardation: mutation screening in Börjeson-Forssman-Lehmann syndrome and MRX27". Am. J. Med. Genet. 100 (1): 43–8. 2001. doi:10.1002/ajmg.1189. PMID 11337747. 
• "Involvement of alpha-PAK-interacting exchange factor in the PAK1-c-Jun NH(2)-terminal kinase 1 activation and apoptosis induced by benzo[apyrene"]. Mol. Cell. Biol. 21 (20): 6796–807. 2001. doi:10.1128/MCB.21.20.6796-6807.2001. PMID 11564864. 
• "The plexin-B1/Rac interaction inhibits PAK activation and enhances Sema4D ligand binding". Genes Dev. 16 (7): 836–45. 2002. doi:10.1101/gad.966402. PMID 11937491. 
• "The Cbl proteins are binding partners for the Cool/Pix family of p21-activated kinase-binding proteins". FEBS Lett. 550 (1–3): 119–23. 2003. doi:10.1016/S0014-5793(03)00853-6. PMID 12935897. 
• "Robust phosphoproteomic profiling of tyrosine phosphorylation sites from human T cells using immobilized metal affinity chromatography and tandem mass spectrometry". Anal. Chem. 76 (10): 2763–72. 2004. doi:10.1021/ac035352d. PMID 15144186. 
• "Large-scale characterization of HeLa cell nuclear phosphoproteins". Proc. Natl. Acad. Sci. U.S.A. 101 (33): 12130–5. 2004. doi:10.1073/pnas.0404720101. PMID 15302935. Bibcode: 2004PNAS..10112130B. 
• "Proteomic, functional, and domain-based analysis of in vivo 14-3-3 binding proteins involved in cytoskeletal regulation and cellular organization". Curr. Biol. 14 (16): 1436–50. 2004. doi:10.1016/j.cub.2004.07.051. PMID 15324660.