Disease relevance of ARHGEF6

• Mutations in ARHGEF6, encoding a guanine nucleotide exchange factor for Rho GTPases, in patients with X-linked mental retardation [1].
• Dimerization of Cool-2 enables its Dbl (diffuse B-cell lymphoma) and pleckstrin homology domains to work together (in trans) to bind specifically to Rac-GDP [2].
• Identification of histological markers for malignant glioma by genome-wide expression analysis: dynein, alpha-PIX and sorcin [3].
• To investigate the role of alpha-PIX in carcinogenesis, we screened 60 cases of gastric cancer for mutations and polymorphisms using an intron-primer that covered all the exons, but no mutations or polymorphisms were found in the coding region [4].

Psychiatry related information on ARHGEF6

• Mutation screening of 119 patients with nonspecific mental retardation revealed a mutation in the first intron of ARHGEF6 (IVS1-11T-->C) in all affected males in a large Dutch family [1].

High impact information on ARHGEF6

• Overall, these findings highlight novel mechanisms by which extracellular signals can direct the specific activation of Rac versus Cdc42 by Cool-2/alpha-Pix [2].
• Novel regulatory mechanisms for the Dbl family guanine nucleotide exchange factor Cool-2/alpha-Pix [2].
• The Cool-2 (cloned-out of library-2) protein (identical to alpha-Pix for Pak-interactive exchange factor) has been implicated in various biological responses including chemoattractant signaling and in certain forms of mental retardation [2].
• In addition, interaction of ARHGEF6 to ARHGEF7 (betaPIX or Cool-1), a close homolog of ARHGEF6, was confirmed [5].
• These data suggest that both the N-terminal calponin homology (CH) and C-terminal coiled-coil domains are necessary for the ARHGEF6-PARVB binding [5].

Biological context of ARHGEF6

• Sequential implication of the mental retardation proteins ARHGEF6 and PAK3 in spine morphogenesis [6].
• We have cloned the rat ARHGEF6 gene and investigated, using a transfection approach, its involvement in spine morphogenesis and its relationship to p21-activated kinase 3 (PAK3) [6].
• Taken together, these results indicate that alphaPIX plays a crucial role in B(a)P-induced apoptosis through activation of the JNK1 pathway kinases [7].
• The open reading frame encodes a polypeptide of 771 amino acids with high homology to human ARHGEF6 [8].
• CONCLUSIONS: We provide evidence for novel mechanisms of allosteric regulation of the Rac-GEF activity of the Cool-2 dimer, involving stimulatory effects by Cdc42 and feedback inhibition by Rac [9].

Anatomical context of ARHGEF6

• We showed by immunofluorescence that ARHGEF6 and PARVB co-localize at the cell periphery to lamellipodia and ruffles in well-spread and actively spreading cells adhered to fibronectin [5].
• We found that expression of tagged ARHGEF6 in hippocampal slice cultures shows a punctate staining in dendritic spines that colocalizes with PSD95 [6].
• Integrin-linked kinase activity regulates Rac- and Cdc42-mediated actin cytoskeleton reorganization via alpha-PIX [10].
• PAK4 and alphaPIX determine podosome size and number in macrophages through localized actin regulation [11].

Associations of ARHGEF6 with chemical compounds

• Together, these data suggest that alphaPIX is a component of early integrin clusters and plays a dual role in integrin-dependent cell spreading [12].

Physical interactions of ARHGEF6

• Moreover, alpha-PAK-interacting exchange factor (alpha PIX) mRNA and its protein expression were upregulated by B(a)P [7].
• BACKGROUND: Cloned-out of library-2 (Cool-2)/PAK-interactive exchange factor (alpha-Pix) was identified through its ability to bind the Cdc42/Rac target p21-activated kinase (PAK) and has been implicated in certain forms of X-linked mental retardation as well as in growth factor- and chemoattractant-coupled signaling pathways [9].

Regulatory relationships of ARHGEF6

• However, unlike many GEFs, Cool-2 binds to activated forms of Cdc42 and Rac [9].
• Deletion of T1 yielded a p85(Cool-1) molecule that mimicked the Cool-2 protein and was capable of strongly stimulating PAK activity [13].

Other interactions of ARHGEF6

• In contrast, it seems that only the coiled-coil domain is required for the interaction and heterodimerization of ARHGEF6 and ARHGEF7 [5].
• The alphaPIX triple domain SH3-DH-PH was found to be required for calpain 4 binding [12].
• Although ARHGEF6 is unlikely to be the gene responsible for either BFLS or MRX27, it remains a prime candidate for nonspecific or syndromic mental retardation linked to Xq26 [14].
• During integrin-dependent spreading of CHO-K1 cells, alphaPIX colocalized with mu- and m-calpain, integrin-linked kinase, and beta1 integrin in early integrin-containing clusters [12].
• Whereas alphaPIX GEF activity contributes to enhanced formation of cellular protrusions, the GEF-independent association with calpain 4 leads to induction of a yet unknown signaling cascade resulting in cell spreading [12].

References