Biology:SORBS1

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

Generic protein structure example

CAP/Ponsin protein, also known as Sorbin and SH3 domain-containing protein 1 is a protein that in humans is encoded by the SORBS1 gene. It is part of a small family of adaptor proteins that regulate cell adhesion, growth factor signaling and cytoskeletal formation. It is mainly expressed in heart, skeletal muscle, liver, adipose tissue, and macrophages; in striated muscle tissue, it is localized to costamere structures.

Structure

CAP/Ponsin may exist as thirteen alternatively-spliced isoforms, ranging from 81 kDa to 142 kDa. It is part of an adaptor protein family, of which ArgBP2 and vinexin are also a part. These proteins contain a conserved sorbin homology (SOHO) domain and three SH3 domains, and CAP/Ponsin is expressed in heart, skeletal muscle, liver, adipose tissue, and macrophages.

Function

In muscle, CAP/Ponsin plays a role in the formation of mature costameres from focal adhesion-like contacts during assembly of the contractile apparatus, as overexpression of CAP/Ponsin disrupted normal cell-matrix contact morphology. In a mouse model of viral myocarditis due to Coxsackievirus infection, CAP/Ponsin stabilized antiviral type I interferon production and was protective against apoptosis and cytotoxicity. It has also been shown to be a major regulator of insulin-stimulated signaling and regulation of glucose uptake, by potentiating insulin-induced phosphorylation and recruitment of CBL to a lipid raft signaling complex involving flotillin. A role for it in macrophage function was illuminated by the finding that, in mice harboring SORBS1-deficient macrophages in bone marrow, it was protective against high-fat diet-induced insulin resistance and showed reduced inflammation. In non-muscle cells, it inhibits cell spreading and focal adhesion turnover, as its siRNA-mediated knockdown resulted in enhanced PAK/MEK/ERK activation and cell migration.

Clinical Significance

CAP/Ponsin was demonstrated to be down-regulated in end-stage heart failure patients; an effect that was restored upon mechanical unloading. A single nucleotide polymorphism in SORBS1 was found to be associated with type 2 diabetes and obesity.

Interactions

SORBS1 has been shown to interact with:

• CBL,
• FLOT1,
• INPPL1,
• INSM1,
• MLLT4,
• PXN, and
• Vinculin.

Further reading

• "[A novel adaptor protein family regulating cytoskeletal organization and signal transduction--Vinexin, CAP/ponsin, ArgBP2]". Seikagaku. The Journal of Japanese Biochemical Society 74 (11): 1356–60. Nov 2002. PMID 12510380. 
• "A role for CAP, a novel, multifunctional Src homology 3 domain-containing protein in formation of actin stress fibers and focal adhesions". The Journal of Biological Chemistry 273 (7): 4073–80. Feb 1998. doi:10.1074/jbc.273.7.4073. PMID 9461600. 
• "Similar and differential behaviour between the nectin-afadin-ponsin and cadherin-catenin systems during the formation and disruption of the polarized junctional alignment in epithelial cells". Genes to Cells 4 (10): 573–81. Oct 1999. doi:10.1046/j.1365-2443.1999.00283.x. PMID 10583506. 
• "Prediction of the coding sequences of unidentified human genes. XVI. The complete sequences of 150 new cDNA clones from brain which code for large proteins in vitro". DNA Research 7 (1): 65–73. Feb 2000. doi:10.1093/dnares/7.1.65. PMID 10718198. 
• "DNA cloning using in vitro site-specific recombination". Genome Research 10 (11): 1788–95. Nov 2000. doi:10.1101/gr.143000. PMID 11076863. 
• "Ataxin-7 interacts with a Cbl-associated protein that it recruits into neuronal intranuclear inclusions". Human Molecular Genetics 10 (11): 1201–13. May 2001. doi:10.1093/hmg/10.11.1201. PMID 11371513. 
• "Cloning, mapping, and characterization of the human sorbin and SH3 domain containing 1 (SORBS1) gene: a protein associated with c-Abl during insulin signaling in the hepatoma cell line Hep3B". Genomics 74 (1): 12–20. May 2001. doi:10.1006/geno.2001.6541. PMID 11374898. http://ntur.lib.ntu.edu.tw/bitstream/246246/162959/1/13.pdf. 
• "The sorbin homology domain: a motif for the targeting of proteins to lipid rafts". Proceedings of the National Academy of Sciences of the United States of America 98 (16): 9098–103. Jul 2001. doi:10.1073/pnas.151252898. PMID 11481476. Bibcode: 2001PNAS...98.9098K. 
• "Molecular scanning of the human sorbin and SH3-domain-containing-1 (SORBS1) gene: positive association of the T228A polymorphism with obesity and type 2 diabetes". Human Molecular Genetics 10 (17): 1753–60. Aug 2001. doi:10.1093/hmg/10.17.1753. PMID 11532984. 
• "The SH2/SH3 adaptor Grb4 transduces B-ephrin reverse signals". Nature 413 (6852): 174–9. Sep 2001. doi:10.1038/35093123. PMID 11557983. Bibcode: 2001Natur.413..174C. 
• "APS facilitates c-Cbl tyrosine phosphorylation and GLUT4 translocation in response to insulin in 3T3-L1 adipocytes". Molecular and Cellular Biology 22 (11): 3599–609. Jun 2002. doi:10.1128/MCB.22.11.3599-3609.2002. PMID 11997497. 
• "The zinc-finger transcription factor INSM1 is expressed during embryo development and interacts with the Cbl-associated protein". Genomics 80 (1): 54–61. Jul 2002. doi:10.1006/geno.2002.6800. PMID 12079283. 
• "Protein-protein interactions between large proteins: two-hybrid screening using a functionally classified library composed of long cDNAs". Genome Research 12 (11): 1773–84. Nov 2002. doi:10.1101/gr.406902. PMID 12421765. 
• "The c-Cbl-associated protein and c-Cbl are two new partners of the SH2-containing inositol polyphosphate 5-phosphatase SHIP2". Biochemical and Biophysical Research Communications 300 (2): 494–500. Jan 2003. doi:10.1016/S0006-291X(02)02894-2. PMID 12504111. 
• "mRNA levels of the insulin-signaling molecule SORBS1 in the adipose depots of nondiabetic women". Obesity Research 11 (4): 586–90. Apr 2003. doi:10.1038/oby.2003.82. PMID 12690089.