Alternative titles; symbols
HGNC Approved Gene Symbol: ARHGEF7
Cytogenetic location: 13q34 Genomic coordinates (GRCh38) : 13:111,114,619-111,305,734 (from NCBI)
By sequencing clones obtained from a size-fractionated immature myeloid leukemia cell line cDNA library, Nagase et al. (1995) cloned ARHGEF7, which they designated KIAA0142. The deduced protein contains 646 amino acids. Northern blot analysis detected highest expression in skeletal muscle and lower expression in all other tissues and cell lines examined.
p21-activated kinases, or PAKs (see PAK1; 602590), bind to and are activated by Rho family GTPases, such as CDC42 (116952) and RAC (see RAC1; 602048). PAKs are implicated in the regulation of gene expression, cytoskeletal architecture, and apoptosis. By screening rat tissue extracts for binding to PAK1, peptide microsequencing, and primer walking, Manser et al. (1998) isolated a rat cDNA encoding Pixb. Pixb is approximately 97% identical to the human cDNA KIAA0142 identified by Nagase et al. (1995). By screening a mouse thymus expression cDNA library, Oh et al. (1997) isolated a cDNA encoding p85SPR (85-kD, SH3 domain-containing, proline-rich protein), which is 93% identical to KIAA0142.
Using a yeast 2-hybrid screen with PAK3 (300142) as bait, Bagrodia ET AL. (1998) also isolated ARHGEF7, which they called COOL1, from a HeLa cell cDNA library. Sequence analysis predicted that the 646-amino acid protein contains an N-terminal SH3 domain, a Dbl-homology (DH) domain, a pleckstrin homology (PH) domain, 2 putative nuclear localization signals, 2 leucine zipper motifs, and a proline-rich region. Northern blot analysis by Manser et al. (1998) revealed ubiquitous expression of an approximately 4.4-kb transcript. By immunofluorescence microscopy, they showed that the SH3 domain of PIXB is required for recruitment of PAK1 to CDC42-driven focal complexes. Their functional analysis demonstrated that PIXB acts as a RAC1 guanine nucleotide exchange factor (GEF) and can induce membrane ruffling.
In NIH3T3 embryonic mouse fibroblasts, Feng et al. (2006) found that Cdc42-Cool1 interactions were necessary for normal EGF receptor (EGFR; 131550) signaling. Cool1 was phosphorylated in an EGF-dependent manner, enabling it to act as a nucleotide exchange factor for Cdc42 and to form a complex with the ubiquitin E3 ligase Cbl (165360), thus regulating Cbl-catalyzed Egfr degradation. The EGF-dependent phosphorylation of Cool1 was transient, but phosphorylation was sustained when Cool1 was ectopically expressed together with insect cell Src (190090). Overexpression of Cool1 augmented Src-induced transformation of NIH3T3 cells, whereas expression of phosphorylation-defective Cool1, as well as knockdown of Cool1 by RNA interference, strongly inhibited cell transformation. Feng et al. (2006) concluded that COOL1 is essential for the regulation of normal EGFR-coupled signaling and for cellular transformation by SRC.
Wang et al. (2014) reported that TIP1 (TAX1BP3; 616484) interacted with ARHGEF7 and rhotekin (RTKN; 602288) and colocalized with ARHGEF7 at the leading edge of migrating T98G human glioblastoma cells. Knockdown of TIP1 via short hairpin RNA did not change the protein content of ARHGEF7 or RTKN in glioblastoma cell lines, but it caused their intracellular redistribution, changed the appearance of T98G cells toward a highly branched morphology, and inhibited cell migration. Knockdown of TIP1 was accompanied by activation of the Rho GTPases RHOA (165390), CDC42, and RAC1 (602048).
By analysis of a human-rodent hybrid cell panel, Nagase et al. (1995) mapped the ARHGEF7 gene to chromosome 13.
Bagrodia, S., Taylor, S. J., Jordon, K. A., Van Aelst, L., Cerione, R. A. A novel regulator of p21-activated kinases. J. Biol. Chem. 273: 23633-23636, 1998. [PubMed: 9726964] [Full Text: https://doi.org/10.1074/jbc.273.37.23633]
Feng, Q., Baird, D., Peng, X., Wang, J., Ly, T., Guan, J.-L., Cerione, R. A. Cool-1 functions as an essential regulatory node for EGF receptor- and Src-mediated cell growth. Nature Cell Biol. 8: 945-956, 2006. [PubMed: 16892055] [Full Text: https://doi.org/10.1038/ncb1453]
Manser, E., Loo, T.-H., Koh, C.-G., Zhao, Z.-S., Chen, X.-Q., Tan, L., Tan, I., Leung, T., Lim, L. PAK kinases are directly coupled to the PIX family of nucleotide exchange factors. Molec. Cell 1: 183-192, 1998. [PubMed: 9659915] [Full Text: https://doi.org/10.1016/s1097-2765(00)80019-2]
Nagase, T., Seki, N., Tanaka, A., Ishikawa, K., Nomura, N. Prediction of the coding sequences of unidentified human genes. IV. The coding sequences of 40 new genes (KIAA0121-KIAA0160) deduced by analysis of cDNA clones from human cell line KG-1. DNA Res. 2: 167-174, 1995. [PubMed: 8590280] [Full Text: https://doi.org/10.1093/dnares/2.4.167]
Oh, W. K., Yoo, J. C., Jo, D., Song, Y. H., Kim, M. G., Park, D. Cloning of a SH3 domain-containing proline-rich protein, p85SPR, and its localization in focal adhesion. Biochem. Biophys. Res. Commun. 235: 794-798, 1997. [PubMed: 9207241] [Full Text: https://doi.org/10.1006/bbrc.1997.6875]
Wang, H., Han, M., Whetsell, W., Jr., Wang, J., Rich, J., Hallahan, D., Han, Z. Tax-interacting protein 1 coordinates the spatiotemporal activation of Rho GTPases and regulates the infiltrative growth of human glioblastoma. Oncogene 33: 1558-1569, 2014. [PubMed: 23563176] [Full Text: https://doi.org/10.1038/onc.2013.97]