E it seems to negatively ML-098 regulate STAT3, even though the exact mechanism by which SOCS6 regulates STAT3 has not been identified [14]. SOCS6 has been shown to handle TCRmediated T cell activation in vitro via damaging regulation of p56lck. SOCS6 was shown to bind towards the kinase domain of active p56lck, targeting it for ubiquitination and subsequent degradation, with SOCS6 overexpression resulting in repression of TCR-dependent IL-2 promoter activity [245]. SOCS6 also seems to negatively regulate signaling of various essential hematopoietic receptor tyrosine kinases. SOCS6 binds towards the juxtamembrane region of c-KIT following stimulation with SCF, thereby regulating activation of members of your MAPK pathway,Am J Clin Exp Immunol 2013;two(1):1-SOCS functionsuch as ERK1/2 and p38 [244]. SOCS6 can also bind to FLT3 and negatively regulate its signaling, decreasing downstream ERK1/2 signaling and concomitant cell proliferation [243]. A prospective role for SOCS6 in neural stem cell differentiation has also been recommended. Expression of SOCS6 was upregulated during differentiation of these cells. SOCS6 overexpression resulted in enhanced neurite outgrowth cells, although siRNA-mediated knockdown of SOCS6 decreased neurite extension [242]. Neurite outgrowth was also enhanced by IGF-1, which enhanced SOCS6 levels, but lowered within the presence of a JAK/STAT pathway inhibitor that could not be rescued by IGF-1 treatment [242]. There is also a large physique of in vitro information supporting a part for SOCS6 in glucose homeostasis. SOCS6 has been shown to inhibit pathways downstream with the INS and IGF-1 receptors [240]. This was facilitated by direct binding of SOCS6 for the IRS-4 adaptor protein following its phosphorylation in response to IGF-1 or insulin and more weakly to IRS-2 in response to IGF-1, permitting it to indirectly associate with all the p85 regulatory subunit of PI3K in response to IGF-1 or insulin stimulation [7, 241]. It has been suggested that the mechanism of regulation in this case may well be by means of stopping recruitment of other downstream signaling proteins [7]. SOCS6 has also been located to interact with PIM3, a protein upregulated in -cells in response to glucose stimulation. Pim3 KO mice showed drastically reduced levels SOCS6 expression in their pancreatic islets, although overexpression of SOCS6 inhibited glucose-induced ERK1/2 activation, suggesting a function for SOCS6 and PIM3 in the damaging regulation of ERK1/2 in response to glucose stimulation [247]. Lowered endogenous SOCS6 in retinal pigment epithelia cells was found to coincide with inhibition of insulin signaling. It has thus been recommended that SOCS6 expression may serve to retain higher basal insulin/AKT signaling in retina and strengthen glucose metabolism [232]. Socs6 KO mice displayed an 8-10 reduction in body weight in comparison to WT littermates, believed to be because of perturbation of IGF-1R signaling [7]. Having said that, despite the in vitro information, Socs6 knockout mice did not show any alterations in glucose metabolism [7]. It has been suggested that this could possibly be as a consequence of compensation by other SOCS household members implicated PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/20008976 in the regulation of insulin receptor signaling, for instance SOCS7 [7] or SOCS1 [80]. Nevertheless, SOCS6 Tg mice using the elongation factor I promoter displayed enhanced AKT activation in response to INS and increased glucose metabolism, supporting an in vivo role for SOCS6 within the regulation of INS signaling [241]. Ultimately, in spite of its expression in the bone marrow, no hematological.