SORBS1

Sorbin and SH3 domain containing 1
PDB rendering based on 2dl3.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2DL3​, 2ECZ​, 2LJ0​, 2LJ1​, 2MOX​, 2O2W​, 2O31​, 2O9S​, 2O9V​, 4LN2​, 4LNP​
Identifiers
Symbols	SORBS1 ; CAP; FLAF2; R85FL; SH3D5; SH3P12; SORB1
External IDs	OMIM: 605264 MGI: 700014 HomoloGene: 83252 GeneCards: SORBS1 Gene
Gene ontology Molecular function • actin binding • SH3/SH2 adaptor activity • insulin receptor binding • protein binding • cytoskeletal protein binding • protein kinase binding Cellular component • stress fiber • nucleus • nucleoplasm • cytoplasm • centrosome • cytosol • plasma membrane • insulin receptor complex • cell-cell adherens junction • zonula adherens • cell-substrate adherens junction • focal adhesion • nuclear matrix • membrane raft Biological process • muscle contraction • cell-matrix adhesion • insulin receptor signaling pathway • positive regulation of signal transduction • glucose transport • cellular response to insulin stimulus • stress fiber assembly • positive regulation of glycogen biosynthetic process • positive regulation of glucose import • positive regulation of lipid biosynthetic process • focal adhesion assembly • positive regulation of establishment of protein localization to plasma membrane Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	10580	20411
Ensembl	ENSG00000095637	ENSMUSG00000025006
UniProt	Q9BX66	Q62417
RefSeq (mRNA)	NM_001034954	NM_001034962
RefSeq (protein)	NP_001030126	NP_001030134
Location (UCSC)	Chr 10: 95.31 – 95.56 Mb	Chr 19: 40.3 – 40.4 Mb
PubMed search

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] CAP/Ponsin is part of a small family of adaptor proteins that regulate cell adhesion, growth factor signaling and cytoskeletal formation. CAP/Ponsin is mainly expressed in heart, skeletal muscle, liver, adipose tissue, and macrophages; in striated muscle tissue, CAP/Ponsin is localized to costamere structures.

Structure

CAP/Ponsin may exist as thirteen alternatively-spliced isoforms, ranging from 81 kDa to 142 kDa.^[4] CAP/Ponsin 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] CAP/Ponsin 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 CAP/Ponsin in macrophage function was illuminated by the finding that mice harboring SORBS1-deficient macrophages in bone marrow was protective against high-fat diet-induced insulin resistance and showed reduced inflammation.^[7] In non-muscle cells, CAP/Ponsin 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][14]
• FLOT1,^[2][13][15]
• INPPL1,^[14]
• INSM1,^[16]
• MLLT4,^[1]
• PXN,^[8] and
• Vinculin.^[1]

References

1. Mandai K, Nakanishi H, Satoh A, Takahashi K, Satoh K, Nishioka H, Mizoguchi A, Takai Y (Mar 1999). "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. doi:10.1083/jcb.144.5.1001. PMC 2148189. PMID 10085297.
2. Baumann CA, Ribon V, Kanzaki M, Thurmond DC, Mora S, Shigematsu S, Bickel PE, Pessin JE, Saltiel AR (Sep 2000). "CAP defines a second signalling pathway required for insulin-stimulated glucose transport". Nature 407 (6801): 202–7. doi:10.1038/35025089. PMID 11001060.
3. "Entrez Gene: SORBS1 sorbin and SH3 domain containing 1".
4. Lin WH, Huang CJ, Liu MW, Chang HM, Chen YJ, Tai TY, Chuang LM (May 2001). "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. doi:10.1006/geno.2001.6541. PMID 11374898.
5. "Vinexin, CAP/ponsin, ArgBP2: a novel adaptor protein family regulating cytoskeletal organization and signal transduction.". Cell Struct Funct 27: 1–7. Feb 2002. doi:10.1247/csf.27.1. PMID 11937713.
6. Ribon V, Printen JA, Hoffman NG, Kay BK, Saltiel AR (Feb 1998). "A novel, multifuntional c-Cbl binding protein in insulin receptor signaling in 3T3-L1 adipocytes". Molecular and Cellular Biology 18 (2): 872–9. doi:10.1128/mcb.18.2.872. PMID 9447983.
7. Lesniewski LA, Hosch SE, Neels JG, de Luca C, Pashmforoush M, Lumeng CN, Chiang SH, Scadeng M, Saltiel AR, Olefsky JM (Apr 2007). "Bone marrow-specific Cap gene deletion protects against high-fat diet-induced insulin resistance". Nature Medicine 13 (4): 455–62. doi:10.1038/nm1550. PMID 17351624.
8. Gehmlich K, Pinotsis N, Hayess K, van der Ven PF, Milting H, El Banayosy A, Körfer R, Wilmanns M, Ehler E, Fürst DO (Jun 2007). "Paxillin and ponsin interact in nascent costameres of muscle cells". Journal of Molecular Biology 369 (3): 665–82. doi:10.1016/j.jmb.2007.03.050. PMID 17462669.
9. Valaperti A, Nishii M, Liu Y, Yang H, Naito K, Liu PP, Eriksson U (May 2014). "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. doi:10.1007/s00395-014-0411-3. PMID 24763933.
10. Baumann CA, Ribon V, Kanzaki M, Thurmond DC, Mora S, Shigematsu S, Bickel PE, Pessin JE, Saltiel AR (Sep 2000). "CAP defines a second signalling pathway required for insulin-stimulated glucose transport". Nature 407 (6801): 202–7. doi:10.1038/35025089. PMID 11001060.
11. Zhang M, Liu J, Cheng A, Deyoung SM, Chen X, Dold LH, Saltiel AR (Nov 2006). "CAP interacts with cytoskeletal proteins and regulates adhesion-mediated ERK activation and motility". The EMBO Journal 25 (22): 5284–93. doi:10.1038/sj.emboj.7601406. PMID 17082770.
12. Lin WH, Chiu KC, Chang HM, Lee KC, Tai TY, Chuang LM (Aug 2001). "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. doi:10.1093/hmg/10.17.1753. PMID 11532984.
13. Haglund K, Ivankovic-Dikic I, Shimokawa N, Kruh GD, Dikic I (May 2004). "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. doi:10.1242/jcs.01148. PMID 15128873.
14. Vandenbroere I, Paternotte N, Dumont JE, Erneux C, Pirson I (Jan 2003). "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. doi:10.1016/s0006-291x(02)02894-2. PMID 12504111.
15. Kimura A, Baumann CA, Chiang SH, Saltiel AR (Jul 2001). "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. doi:10.1073/pnas.151252898. PMC 55379. PMID 11481476.
16. Xie J, Cai T, Zhang H, Lan MS, Notkins AL (Jul 2002). "The zinc-finger transcription factor INSM1 is expressed during embryo development and interacts with the Cbl-associated protein". Genomics 80 (1): 54–61. doi:10.1006/geno.2002.6800. PMC 1237014. PMID 12079283.

Further reading

• Kioka N (Nov 2002). "[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. PMID 12510380.
• Ribon V, Herrera R, Kay BK, Saltiel AR (Feb 1998). "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. doi:10.1074/jbc.273.7.4073. PMID 9461600.
• Asakura T, Nakanishi H, Sakisaka T, Takahashi K, Mandai K, Nishimura M, Sasaki T, Takai Y (Oct 1999). "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. doi:10.1046/j.1365-2443.1999.00283.x. PMID 10583506.
• Nagase T, Kikuno R, Ishikawa KI, Hirosawa M, Ohara O (Feb 2000). "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. doi:10.1093/dnares/7.1.65. PMID 10718198.
• Hartley JL, Temple GF, Brasch MA (Nov 2000). "DNA cloning using in vitro site-specific recombination". Genome Research 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
• 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 (May 2001). "Ataxin-7 interacts with a Cbl-associated protein that it recruits into neuronal intranuclear inclusions". Human Molecular Genetics 10 (11): 1201–13. doi:10.1093/hmg/10.11.1201. PMID 11371513.
• Lin WH, Huang CJ, Liu MW, Chang HM, Chen YJ, Tai TY, Chuang LM (May 2001). "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. doi:10.1006/geno.2001.6541. PMID 11374898.
• Kimura A, Baumann CA, Chiang SH, Saltiel AR (Jul 2001). "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. doi:10.1073/pnas.151252898. PMC 55379. PMID 11481476.
• Lin WH, Chiu KC, Chang HM, Lee KC, Tai TY, Chuang LM (Aug 2001). "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. doi:10.1093/hmg/10.17.1753. PMID 11532984.
• Cowan CA, Henkemeyer M (Sep 2001). "The SH2/SH3 adaptor Grb4 transduces B-ephrin reverse signals". Nature 413 (6852): 174–9. doi:10.1038/35093123. PMID 11557983.
• Liu J, Kimura A, Baumann CA, Saltiel AR (Jun 2002). "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. doi:10.1128/MCB.22.11.3599-3609.2002. PMC 133825. PMID 11997497.
• Xie J, Cai T, Zhang H, Lan MS, Notkins AL (Jul 2002). "The zinc-finger transcription factor INSM1 is expressed during embryo development and interacts with the Cbl-associated protein". Genomics 80 (1): 54–61. doi:10.1006/geno.2002.6800. PMC 1237014. PMID 12079283.
• Nakayama M, Kikuno R, Ohara O (Nov 2002). "Protein-protein interactions between large proteins: two-hybrid screening using a functionally classified library composed of long cDNAs". Genome Research 12 (11): 1773–84. doi:10.1101/gr.406902. PMC 187542. PMID 12421765.
• Vandenbroere I, Paternotte N, Dumont JE, Erneux C, Pirson I (Jan 2003). "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. doi:10.1016/S0006-291X(02)02894-2. PMID 12504111.
• Yang WS, Lee WJ, Huang KC, Lee KC, Chao CL, Chen CL, Tai TY, Chuang LM (Apr 2003). "mRNA levels of the insulin-signaling molecule SORBS1 in the adipose depots of nondiabetic women". Obesity Research 11 (4): 586–90. doi:10.1038/oby.2003.82. PMID 12690089.