SOCS6 is a selective suppressor of receptor tyrosine kinase signaling
- 425 Downloads
The suppressors of cytokine signaling (SOCS) are well-known negative regulators of cytokine receptor signaling. SOCS6 is one of eight members of the SOCS family of proteins. Similar to other SOCS proteins, SOCS6 consists of an uncharacterized extended N-terminal region followed by an SH2 domain and a SOCS box. Unlike other SOCS proteins, SOCS6 is mainly involved in negative regulation of receptor tyrosine kinase signaling. SOCS6 is widely expressed in many tissues and is found to be downregulated in many cancers including colorectal cancer, gastric cancer, lung cancer, ovarian cancer, stomach cancer, thyroid cancer, hepatocellular carcinoma, and pancreatic cancer. SOCS6 is involved in negative regulation of receptor signaling by increasing degradation mediated by ubiquitination of receptors or substrate proteins and induces apoptosis by targeting mitochondrial proteins. Therefore, SOCS6 turns out as an important regulator of survival signaling and its activity is required for controlling receptor tyrosine kinase signaling.
KeywordsSOCS FLT3 KIT INSR SCF Insulin FL
This research was funded by the Stiftelsen Olle Engkvist Byggmästare, Kungliga Fysiografiska Sällskapet i Lund, Ollie and Elof Ericssons Stiftelse and Stiftelsen Lars Hiertas Minne.
Conflicts of interest
- 1.Kazi JU, Kabir NN, Flores-Morales A, Rönnstrand L. SOCS proteins in regulation of receptor tyrosine kinase signaling. Cell Mol Life Sci. 2014;71:3297–310.Google Scholar
- 3.Kazi JU, Sun J, Phung B, Zadjali F, Flores-Morales A, Rönnstrand L. Suppressor of cytokine signaling 6 (SOCS6) negatively regulates Flt3 signal transduction through direct binding to phosphorylated tyrosines 591 and 919 of Flt3. J Biol Chem. 2012;287:36509–17.PubMedCentralPubMedCrossRefGoogle Scholar
- 4.Zadjali F, Pike AC, Vesterlund M, Sun J, Wu C, Li SS, et al. Structural basis for c-Kit inhibition by the suppressor of cytokine signaling 6 (SOCS6) ubiquitin ligase. J Biol Chem. 2011;286:480–90.Google Scholar
- 5.Bayle J, Letard S, Frank R, Dubreuil P, De Sepulveda P. Suppressor of cytokine signaling 6 associates with Kit and regulates Kit receptor signaling. J Biol Chem. 2004;279:12249–59.Google Scholar
- 13.Xia L, Wang L, Chung AS, Ivanov SS, Ling MY, Dragoi AM, et al. Identification of both positive and negative domains within the epidermal growth factor receptor COOH-terminal region for signal transducer and activator of transcription (STAT) activation. J Biol Chem. 2002;277:30716–23.PubMedCrossRefGoogle Scholar
- 27.Hwang MN, Ha TH, Park J, Shim J, Lee H, Kim YN, et al. Increased SOCS6 stability with PMA requires its N-terminal region and the Erk pathway via PKC delta activation. Biochem Biophys Res Commun. 2007;354:184–9.Google Scholar
- 29.Kazi JU. The mechanism of protein kinase C regulation. Front Biol. 2011;6:328–36.Google Scholar
- 30.Kazi JU, Kim CR, Soh JW. Subcellular localization of diacylglycerol-responsive protein kinase C isoforms in HeLa cells. Bull Kor Chem Soc. 2009;30:1981–4.Google Scholar
- 33.Piao L, Park J, Li Y, Shin S, Shin S, Kong G, et al. SOCS3 and SOCS6 are required for the risperidone-mediated inhibition of insulin and leptin signaling in neuroblastoma cells. Int J Mol Med. 2014;33:1364–70.Google Scholar
- 38.Tanaka T, Arai M, Jiang X, Sugaya S, Kanda T, Fujii K, et al. Downregulation of microRNA-431 by human interferon-beta inhibits viability of medulloblastoma and glioblastoma cells via upregulation of SOCS6. Int J Oncol. 2014;44:1685–90.Google Scholar
- 39.Wu Q, Luo G, Yang Z, Zhu F, An Y, Shi Y, et al. Mir-17-5p promotes proliferation by targeting SOCS6 in gastric cancer cells. FEBS Lett. 2014;588:2055–62.Google Scholar
- 47.Sattler M, Salgia R, Shrikhande G, Verma S, Pisick E, Prasad KV, et al. Steel factor induces tyrosine phosphorylation of CRKL and binding of CRKL to a complex containing c-Kit, phosphatidylinositol 3-kinase, and p120(CBL). J Biol Chem. 1997;272:10248–53.Google Scholar
- 48.Fang D, Wang HY, Fang N, Altman Y, Elly C, Liu YC. Cbl-b, a RING-type E3 ubiquitin ligase, targets phosphatidylinositol 3-kinase for ubiquitination in T cells. J Biol Chem. 2001;276:4872–8.Google Scholar
- 49.Lennartsson J, Rönnstrand L. Stem cell factor receptor/c-Kit: from basic science to clinical implications. Physiol Rev. 2012;92:1619–49.Google Scholar
- 50.Kazi JU, Agarwal S, Sun J, Bracco E, Rönnstrand L. Src-like-adaptor protein (SLAP) differentially regulates normal and oncogenic c-Kit signaling. J Cell Sci. 2014;127:653–62.Google Scholar
- 51.Sun J, Mohlin S, Lundby A, Kazi JU, Hellman U, Påhlman S, et al. The PI3-kinase isoform p110delta is essential for cell transformation induced by the D816V mutant of c-Kit in a lipid-kinase-independent manner. Oncogene. 2013. doi: 10.1038/onc.2013.479.
- 54.Kabir NN, Rönnstrand L, Kazi JU. Flt3 mutations in patients with childhood acute lymphoblastic leukemia (ALL). Med Oncol. 2013;30:462.Google Scholar
- 55.Ben-Yair L, Slaaby R, Herman A, Cohen Y, Biener E, Moran N, et al. Preparation and expression of biologically active prolactin and growth hormone receptors and suppressor of cytokine signaling proteins 1, 2, 3, and 6 tagged with cyan and yellow fluorescent proteins. Protein Expr Purif. 2002;25:456–64.PubMedCrossRefGoogle Scholar