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HGNC Approved Gene Symbol: SORBS3
Cytogenetic location: 8p21.3 Genomic coordinates (GRCh38) : 8:22,544,973-22,575,788 (from NCBI)
The SORBS3 gene encodes 2 isoforms vinexin-alpha and -beta that are vinculin (VCL; 193065)-binding cytoskeletal proteins involved in focal adhesion and cell-cell adhesion (Kioka et al., 1999).
Using yeast 2-hybrid analysis with chicken vinculin as bait to screen a human placenta cDNA library, followed by screening a human HeLa cDNA library with a vinculin-binding cDNA fragment, Kioka et al. (1999) cloned a partial SORBS3 cDNA. They cloned full-length and partial mouse Sorbs3 cDNAs that encode mouse vinexin-alpha and -beta. The 733-amino acid mouse vinexin-alpha and the 328-amino acid mouse vinexin-beta have deduced molecular masses of 87 kD and 37 kD, respectively. Sequence analysis of the 5-prime UTRs of the human and mouse cDNAs, suggested that 2 distinct alternative promoters give rise to the 2 mRNA species. Vinexin-beta corresponds to the C-terminal half of vinexin-alpha, and both species share a region containing 3 SH3 domains. Northern blot analysis detected a 2.0-kb transcript in all human tissues examined with highest expression in heart, placenta, and pancreas, moderate expression in brain and liver, and low expression in lung, skeletal muscle, and kidney. A 3.0-kb transcript was expressed in skeletal muscle, heart, brain, placenta, and pancreas at lower levels than the 2.0-kb transcript. Only the 2.0-kb transcript was detected in HeLa cells, consistent with isolation of this cDNA from the HeLa cell cDNA library. Both mouse vinexin isoforms localized primarily to focal adhesions in NIH3T3 cells, with lower levels of vinexin-beta also found in the cytoplasm and nucleus, and both isoforms also localized to cell-cell adhesions in porcine epithelial cells.
By in vitro GST binding and in vivo yeast 2-hybrid assays, Kioka et al. (1999) showed that the region between the first and second SH3 domains mediated binding to vinculin. Vinexin-beta enhanced cell-spreading activity when expressed in mouse myoblastic cells.
Using Western blot analysis and immune complex kinase assays, Suwa et al. (2002) determined that expression of vinexin-beta allowed anchorage-independent ERK2 (MAPK1; 176948) activation stimulated by EGF (131530). In contrast, expression of vinexin-beta had no effect on ERK2 activation in adherent cells, suggesting that vinexin-beta regulates the anchorage dependence of ERK2 activation. Deletion analysis showed that the region between the second and third SH3 domains is required for this function.
Using Western blot analysis with phosphospecific antibodies, Mitsushima et al. (2006) found that vinexin-beta expressed in COS-7 cells enhanced phosphorylation of EGFR (131550) tyrosine residues in a cell type-specific manner. Vinexin-beta did not stimulate EGFR phosphorylation but suppressed its dephosphorylation, resulting in sustained phosphorylation. Deletion analysis showed that the first and third SH3 domains of vinexin-beta were required for inducing sustained EGFR phosphorylation. By subcellular distribution and immunoprecipitation analysis, they demonstrated that vinexin-beta increased phosphorylated EGFR on the cell surface in a c-Cbl (CBL; 165360)-dependent manner, without altering EGFR phosphorylation in the cytosol. Knockdown of vinexin-beta with siRNA reduced phosphorylation of EGFR on the plasma membrane. Mitsushima et al. (2006) proposed that expression of vinexin-beta decreases the amount of CBL in the cytosol and delays EGFR endocytosis, leading to sustained phosphorylation of EGFR on the cell surface.
Gross (2014) mapped the SORBS3 gene to chromosome 8p21.3 based on an alignment of the SORBS3 sequence (GenBank AF064807) with the genomic sequence (GRCh37).
Gross, M. B. Personal Communication. Baltimore, Md. 5/30/2014.
Kioka, N., Sakata, S., Kawauchi, T., Amachi, T., Akiyama, S. K., Okazaki, K., Yaen, C., Yamada, K. M., Aota, S. Vinexin: a novel vinculin-binding protein with multiple SH3 domains enhances actin cytoskeletal organization. J. Cell Biol. 144: 59-69, 1999. [PubMed: 9885244] [Full Text: https://doi.org/10.1083/jcb.144.1.59]
Mitsushima, M., Ueda, K., Kioka, N. Vinexin-beta regulates the phosphorylation of epidermal growth factor receptor on the cell surface. Genes Cells 11: 971-982, 2006. [PubMed: 16923119] [Full Text: https://doi.org/10.1111/j.1365-2443.2006.00995.x]
Suwa, A., Mitsushima, M., Ito, T., Akamatsu, M., Ueda, K., Amachi, T., Kioka, N. Vinexin-beta regulates the anchorage dependence of ERK2 activation stimulated by epidermal growth factor. J. Biol. Chem. 277: 13053-13058, 2002. [PubMed: 11825889] [Full Text: https://doi.org/10.1074/jbc.M108644200]