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ARHGEF6  -  Rac/Cdc42 guanine nucleotide exchange...

Homo sapiens

Synonyms: Alpha-Pix, COOL-2, COOL2, Cool-2, Cool2, ...
 
 
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Disease relevance of ARHGEF6

 

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

 

Anatomical context of ARHGEF6

 

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

  1. Mutations in ARHGEF6, encoding a guanine nucleotide exchange factor for Rho GTPases, in patients with X-linked mental retardation. Kutsche, K., Yntema, H., Brandt, A., Jantke, I., Nothwang, H.G., Orth, U., Boavida, M.G., David, D., Chelly, J., Fryns, J.P., Moraine, C., Ropers, H.H., Hamel, B.C., van Bokhoven, H., Gal, A. Nat. Genet. (2000) [Pubmed]
  2. Novel regulatory mechanisms for the Dbl family guanine nucleotide exchange factor Cool-2/alpha-Pix. Feng, Q., Baird, D., Cerione, R.A. EMBO J. (2004) [Pubmed]
  3. Identification of histological markers for malignant glioma by genome-wide expression analysis: dynein, alpha-PIX and sorcin. Yokota, T., Kouno, J., Adachi, K., Takahashi, H., Teramoto, A., Matsumoto, K., Sugisaki, Y., Onda, M., Tsunoda, T. Acta Neuropathol. (2006) [Pubmed]
  4. Genomic structure of human alpha-pix, and variable deletions in a poly (T) tract in gastric cancer tissue. Wang, Y.J., Oba, S.M., Yoshii, S., Song, J.P., Wang, Y., Kanamori, M., Ota, S., Tanaka, M., Sugimura, H. Cancer Lett. (2001) [Pubmed]
  5. Interaction of alphaPIX (ARHGEF6) with beta-parvin (PARVB) suggests an involvement of alphaPIX in integrin-mediated signaling. Rosenberger, G., Jantke, I., Gal, A., Kutsche, K. Hum. Mol. Genet. (2003) [Pubmed]
  6. Sequential implication of the mental retardation proteins ARHGEF6 and PAK3 in spine morphogenesis. Nod??-Langlois, R., Muller, D., Boda, B. J. Cell. Sci. (2006) [Pubmed]
  7. Involvement of alpha-PAK-interacting exchange factor in the PAK1-c-Jun NH(2)-terminal kinase 1 activation and apoptosis induced by benzo[a]pyrene. Yoshii, S., Tanaka, M., Otsuki, Y., Fujiyama, T., Kataoka, H., Arai, H., Hanai, H., Sugimura, H. Mol. Cell. Biol. (2001) [Pubmed]
  8. The mouse Arhgef6 gene: cDNA sequence, expression analysis, and chromosome assignment. Kutsche, K., Gal, A. Cytogenet. Cell Genet. (2001) [Pubmed]
  9. The Cool-2/alpha-Pix protein mediates a Cdc42-Rac signaling cascade. Baird, D., Feng, Q., Cerione, R.A. Curr. Biol. (2005) [Pubmed]
  10. Integrin-linked kinase activity regulates Rac- and Cdc42-mediated actin cytoskeleton reorganization via alpha-PIX. Filipenko, N.R., Attwell, S., Roskelley, C., Dedhar, S. Oncogene (2005) [Pubmed]
  11. PAK4 and alphaPIX determine podosome size and number in macrophages through localized actin regulation. Gringel, A., Walz, D., Rosenberger, G., Minden, A., Kutsche, K., Kopp, P., Linder, S. J. Cell. Physiol. (2006) [Pubmed]
  12. AlphaPIX associates with calpain 4, the small subunit of calpain, and has a dual role in integrin-mediated cell spreading. Rosenberger, G., Gal, A., Kutsche, K. J. Biol. Chem. (2005) [Pubmed]
  13. Regulation of the Cool/Pix proteins: key binding partners of the Cdc42/Rac targets, the p21-activated kinases. Feng, Q., Albeck, J.G., Cerione, R.A., Yang, W. J. Biol. Chem. (2002) [Pubmed]
  14. 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. Lower, K.M., Gecz, J. Am. J. Med. Genet. (2001) [Pubmed]
 
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