Spelling suggestions: "subject:"cytokines signalling 3 (SOCS3)""
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Interaction of suppressor of cytokine signalling 3 with cavin-1 links SOCS3 function and cavin-1 stabilityWilliams, Jamie J.L., Alotaiq, N., Mullen, W., Burchmore, R., Liu, L., Baillie, G.S., Schaper, F., Pilch, P.F., Palmer, Timothy M. 12 January 2018 (has links)
Yes / Effective suppression of JAK–STAT signalling by the inducible inhibitor “suppressor of
cytokine signalling 3” (SOCS3) is essential for limiting signalling from cytokine receptors.
Here we show that cavin-1, a component of caveolae, is a functionally significant SOCS3-
interacting protein. Biochemical and confocal imaging demonstrate that SOCS3 localisation to
the plasma membrane requires cavin-1. SOCS3 is also critical for cavin-1 stabilisation, such
that deletion of SOCS3 reduces the expression of cavin-1 and caveolin-1 proteins, thereby
reducing caveola abundance in endothelial cells. Moreover, the interaction of cavin-1 and
SOCS3 is essential for SOCS3 function, as loss of cavin-1 enhances cytokine-stimulated
STAT3 phosphorylation and abolishes SOCS3-dependent inhibition of IL-6 signalling by cyclic
AMP. Together, these findings reveal a new functionally important mechanism linking
SOCS3-mediated inhibition of cytokine signalling to localisation at the plasma membrane via
interaction with and stabilisation of cavin-1. / This work was supported by project grants to T.M.P. from the Chief Scientist Office (ETM/226), British Heart Foundation (PG12/1/ 29276, PG 14/32/30812), and a National Health Service Greater Glasgow and Clyde Research Endowment Fund (2011REFCH08). P.F.P. was supported by the National Institutes of Health grant DK097708. J.J.L.W. was supported by a doctoral training studentship from the Biotechnology and Biological Sciences Research Council Doctoral Training Programme in Biochemistry and Molecular Biology at the University of Glasgow (BB/F016735/1). N.A. was supported by a Saudi Government PhD Scholarship. This work was also supported in part by equipment grants to T.M.P. from Diabetes UK (BDA 11/0004309) and Alzheimer’s Research UK (ARUK-EG2016A-3).
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Suppressor of cytokine signalling 3 (SOCS3) turnover and regulation of human saphenous vein smooth muscle cell signalling and functionMoshapa, Florah T. January 2021 (has links)
Neointimal hyperplasia (NIH) is a cardiovascular disease characterised by increased smooth muscle cell (SMC) inflammation and proliferation. Suppressor of cytokine signalling 3 (SOCS3) limits Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways involved in vascular remodelling but is limited by its short biological half-life. Therefore, mutation of all 9 Lys residues that are potential sites of ubiquitylation to Arg should produce a mutated SOCS3 resistant to ubiquitin-mediated proteasomal degradation (“Lys-less” SOCS3). This study hypothesise that enhancing SOCS3 stability and limiting JAK/STAT signalling may provide sustained inhibition of the vascular remodelling in NIH.
Lentiviral transduction of WT and Lys-less SOCS3 in human saphenous vein (HSVSMCs) was highly efficient after 48 hours (>97%) and was sustained over 2 weeks. Lys-less SOCS3 was resistant to ubiquitylation contrary to WT-transduced HSVECs, and Lys-less SOCS3 was more stable (t1/2=4h) than WT (t1/2<4h) (n=6, P<0.001) in HSVSMCs. In HSVSMCs, both Lys-less SOCS3 and WT inhibited sIL-6Rα/IL-6 mediated STAT3 activation but not extracellular signal regulated protein kinase 1/2 (ERK1/2) by 80±7% (Lys-lessSOCS3/pSTAT3) and 74±6% (WT/pSTAT3) (n=3, P<0.05) and similarly inhibited PDGF-mediated STAT3 activation but not ERK1/2 by 67±17% (Lys-less SOCS3/pSTAT3) and 72±18% (WT/pSTAT3) (n=3, P<0.05). Functionally, Lys-less SOCS3 and WT were equivalent in inhibiting sIL-6Rα/IL-6 and PDGF-induced proliferation, whilst having no effects on PDGF-induced migration in HSVSMCs.
Lys-less SOCS3 can be successfully transduced into primary HSVSMCs. It is more stable than WT yet retains its functional ability to ameliorate pro-inflammatory signalling and SMC proliferation, making it an attractive option for developing treatment of NIH. / University of Botswana
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