SORBS1 explained

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.^{[1] [2] [3]} 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.^[4] It is part of an adaptor protein family, of which ArgBP2 and vinexin are also a part.^[5] 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.^{[4] [6] [7]}

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.^[8] 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.^[9] 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.^[10] 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.^[7] 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.^[11]

Clinical Significance

CAP/Ponsin was demonstrated to be down-regulated in end-stage heart failure patients; an effect that was restored upon mechanical unloading.^[8] A single nucleotide polymorphism in SORBS1 was found to be associated with type 2 diabetes and obesity.^[12]

Interactions

SORBS1 has been shown to interact with:

• CBL,^[13]
• FLOT1,^{[14] [15]}
• INPPL1,^[13]
• INSM1,^[16]
• MLLT4,^[1]
• PXN,^[8] and
• Vinculin.

Further reading

• Kioka N . [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 . 12510380 .
• Ribon V, Herrera R, Kay BK, Saltiel AR . 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 . 9461600 . 10.1074/jbc.273.7.4073 . free .
• Asakura T, Nakanishi H, Sakisaka T, Takahashi K, Mandai K, Nishimura M, Sasaki T, Takai Y . 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 . 10583506 . 10.1046/j.1365-2443.1999.00283.x . 24023429 . free .
• Nagase T, Kikuno R, Ishikawa KI, Hirosawa M, Ohara O . 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 . 10718198 . 10.1093/dnares/7.1.65 . free .
• Hartley JL, Temple GF, Brasch MA . DNA cloning using in vitro site-specific recombination . Genome Research . 10 . 11 . 1788–95 . Nov 2000 . 11076863 . 310948 . 10.1101/gr.143000 .
• Lebre AS, Jamot L, Takahashi J, Spassky N, Leprince C, Ravisé N, Zander C, Fujigasaki H, Kussel-Andermann P, Duyckaerts C, Camonis JH, Brice A . Ataxin-7 interacts with a Cbl-associated protein that it recruits into neuronal intranuclear inclusions . Human Molecular Genetics . 10 . 11 . 1201–13 . May 2001 . 11371513 . 10.1093/hmg/10.11.1201 . free .
• Lin WH, Huang CJ, Liu MW, Chang HM, Chen YJ, Tai TY, Chuang LM . 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 . 11374898 . 10.1006/geno.2001.6541 .
• Kimura A, Baumann CA, Chiang SH, Saltiel AR . 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 . 11481476 . 55379 . 10.1073/pnas.151252898 . 2001PNAS...98.9098K . free .
• Lin WH, Chiu KC, Chang HM, Lee KC, Tai TY, Chuang LM . 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 . 11532984 . 10.1093/hmg/10.17.1753 . free .
• Cowan CA, Henkemeyer M . The SH2/SH3 adaptor Grb4 transduces B-ephrin reverse signals . Nature . 413 . 6852 . 174–9 . Sep 2001 . 11557983 . 10.1038/35093123 . 2001Natur.413..174C . 4313061 .
• Liu J, Kimura A, Baumann CA, Saltiel AR . 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 . 11997497 . 133825 . 10.1128/MCB.22.11.3599-3609.2002 .
• Xie J, Cai T, Zhang H, Lan MS, Notkins AL . 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 . 12079283 . 1237014 . 10.1006/geno.2002.6800 .
• Nakayama M, Kikuno R, Ohara O . 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 . 12421765 . 187542 . 10.1101/gr.406902 .
• Vandenbroere I, Paternotte N, Dumont JE, Erneux C, Pirson I . 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 . 12504111 . 10.1016/S0006-291X(02)02894-2 .
• Yang WS, Lee WJ, Huang KC, Lee KC, Chao CL, Chen CL, Tai TY, Chuang LM . mRNA levels of the insulin-signaling molecule SORBS1 in the adipose depots of nondiabetic women . Obesity Research . 11 . 4 . 586–90 . Apr 2003 . 12690089 . 10.1038/oby.2003.82 . free .

Notes and References

1. Mandai K, Nakanishi H, Satoh A, Takahashi K, Satoh K, Nishioka H, Mizoguchi A, Takai Y . Ponsin/SH3P12: an l-afadin- and vinculin-binding protein localized at cell-cell and cell-matrix adherens junctions . The Journal of Cell Biology . 144 . 5 . 1001–17 . Mar 1999 . 10085297 . 2148189 . 10.1083/jcb.144.5.1001 .
2. Baumann CA, Ribon V, Kanzaki M, Thurmond DC, Mora S, Shigematsu S, Bickel PE, Pessin JE, Saltiel AR . CAP defines a second signalling pathway required for insulin-stimulated glucose transport . Nature . 407 . 6801 . 202–7 . Sep 2000 . 11001060 . 10.1038/35025089 . 2000Natur.407..202B . 2027.42/62940 . 4334519 . free .
3. Web site: Entrez Gene: SORBS1 sorbin and SH3 domain containing 1.
4. Lin WH, Huang CJ, Liu MW, Chang HM, Chen YJ, Tai TY, Chuang LM . 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 . 11374898 . 10.1006/geno.2001.6541 .
5. 11937713 . 10.1247/csf.27.1 . 27 . Vinexin, CAP/ponsin, ArgBP2: a novel adaptor protein family regulating cytoskeletal organization and signal transduction. . Feb 2002 . Cell Struct Funct . 1–7 . Kioka N, Ueda K, Amachi T. 1 . free .
6. Ribon V, Printen JA, Hoffman NG, Kay BK, Saltiel AR . A novel, multifuntional c-Cbl binding protein in insulin receptor signaling in 3T3-L1 adipocytes . Molecular and Cellular Biology . 18 . 2 . 872–9 . Feb 1998 . 9447983 . 10.1128/mcb.18.2.872 . 108798.
7. Lesniewski LA, Hosch SE, Neels JG, de Luca C, Pashmforoush M, Lumeng CN, Chiang SH, Scadeng M, Saltiel AR, Olefsky JM . Bone marrow-specific Cap gene deletion protects against high-fat diet-induced insulin resistance . Nature Medicine . 13 . 4 . 455–62 . Apr 2007 . 17351624 . 10.1038/nm1550 . 22210202 .
8. Gehmlich K, Pinotsis N, Hayess K, van der Ven PF, Milting H, El Banayosy A, Körfer R, Wilmanns M, Ehler E, Fürst DO . Paxillin and ponsin interact in nascent costameres of muscle cells . Journal of Molecular Biology . 369 . 3 . 665–82 . Jun 2007 . 17462669 . 10.1016/j.jmb.2007.03.050 .
9. Valaperti A, Nishii M, Liu Y, Yang H, Naito K, Liu PP, Eriksson U . The adapter protein c-Cbl-associated protein (CAP) protects from acute CVB3-mediated myocarditis through stabilization of type I interferon production and reduced cytotoxicity . Basic Research in Cardiology . 109 . 3 . 411 . May 2014 . 24763933 . 10.1007/s00395-014-0411-3 . 23062795 .
10. Baumann CA, Ribon V, Kanzaki M, Thurmond DC, Mora S, Shigematsu S, Bickel PE, Pessin JE, Saltiel AR . CAP defines a second signalling pathway required for insulin-stimulated glucose transport . Nature . 407 . 6801 . 202–7 . Sep 2000 . 11001060 . 10.1038/35025089 . 2000Natur.407..202B . 2027.42/62940 . 4334519 . free .
11. Zhang M, Liu J, Cheng A, Deyoung SM, Chen X, Dold LH, Saltiel AR . CAP interacts with cytoskeletal proteins and regulates adhesion-mediated ERK activation and motility . The EMBO Journal . 25 . 22 . 5284–93 . Nov 2006 . 17082770 . 10.1038/sj.emboj.7601406 . 1636617.
12. Lin WH, Chiu KC, Chang HM, Lee KC, Tai TY, Chuang LM . 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 . 11532984 . 10.1093/hmg/10.17.1753. free .
13. Vandenbroere I, Paternotte N, Dumont JE, Erneux C, Pirson I . 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 . 12504111 . 10.1016/s0006-291x(02)02894-2.
14. Haglund K, Ivankovic-Dikic I, Shimokawa N, Kruh GD, Dikic I . Recruitment of Pyk2 and Cbl to lipid rafts mediates signals important for actin reorganization in growing neurites . Journal of Cell Science . 117 . Pt 12 . 2557–68 . May 2004 . 15128873 . 10.1242/jcs.01148 . 14083271 .
15. Kimura A, Baumann CA, Chiang SH, Saltiel AR . 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 . 11481476 . 55379 . 10.1073/pnas.151252898 . 2001PNAS...98.9098K . free .
16. Xie J, Cai T, Zhang H, Lan MS, Notkins AL . 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 . 12079283 . 1237014 . 10.1006/geno.2002.6800.