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Abstract
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.
Highlights
Effective suppression of Janus kinases (JAKs)–signal transducer and activators of transcription (STATs) signalling by the inducible inhibitor “suppressor of cytokine signalling 3” (SOCS3) is essential for limiting signalling from cytokine receptors
As well as inhibiting cytokine receptor signalling by inhibiting the Tyr kinase activity of receptor-bound JAKs19, SOCS3 can control the stability of SH2 domain-bound proteins as part of an elongin/ cullin/SOCS3 (ECSSOCS3) E3 ubiquitin ligase complex[6,7,20]
The importance of SOCS3 in limiting downstream signalling from cytokine receptor complexes that utilise gp[130], as well as the leptin receptor ObRb and the granulocyte colony-stimulating factor receptor (G-CSFR), is well established[6,7] relatively little is known about how SOCS3 interaction with other intracellular proteins can impact on its ability to inhibit signalling
Summary
Effective suppression of JAK–STAT signalling by the inducible inhibitor “suppressor of cytokine signalling 3” (SOCS3) is essential for limiting signalling from cytokine receptors. 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. CUE domain-containing 2 (CUEDC2) was identified as a novel SOCS3-interacting protein that could enhance its interaction with elongin C11 Such observations raise the possibility that additional protein interactors may be required to maximise the ability of SOCS3 to regulate signalling. Cavin-1, which is one of a family of four related proteins (cavins 1 to 4), is recruited by one or more “caveolin” proteins (caveolins 1 to 3) to the plasma membrane during the latter stages of caveola biogenesis, and is thought to be essential for caveola formation by stabilising caveolin proteins at the plasma membrane[14]
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