Suppressor of Cytokine Signaling (SOCS) 5 Utilises Distinct Domains for Regulation of JAK1 and Interaction with the Adaptor Protein Shc-1

Linossi, Edmond M.; Chandrashekaran, Indu R.; Kolesnik, Tatiana B.; Murphy, James M.; Webb, Andrew I.; Willson, Tracy A.; Kędzierski, Łukasz; Bullock, Alex N.; Babon, Jeffrey J.; Norton, Raymond S.; Nicola, Nicos A.; Nicholson, Sandra E.

doi:10.1371/journal.pone.0070536

Cited by 45 publications

(64 citation statements)

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“…In addition to regulating degradation of the EGFR, SOCS5 also accelerates degradation of ErbB2 and ErbB4 [59]. Furthermore, SOCS5 associates following growth factor stimulation with Shc1 at pY317 through its SH2 domain [62] suggesting that SOCS5 not only limits receptor stability but also induces degradation of downstream signaling proteins. SOCS5 also weakly associates with KIT but its role in KIT regulation has not been studied [18].…”

Section: Socs5mentioning

confidence: 99%

SOCS proteins in regulation of receptor tyrosine kinase signaling

Kazi

Kabir

Flores‐Morales

2014

Cell. Mol. Life Sci.

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SOCS proteins in regulation of receptor tyrosine kinase signaling.Uddin, Kazi; Kabir, Nuzhat N; Flores-Morales, Amilcar; Rönnstrand, Lars Link to publication Citation for published version (APA): Kazi, J. U., Kabir, N. N., Flores-Morales, A., & Rönnstrand, L. (2014). SOCS proteins in regulation of receptor tyrosine kinase signaling. Cellular and Molecular Life Sciences, 71(17), 3297-3310. DOI: 10.1007/s00018-014-1619-y General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. AbstractThe receptor tyrosine kinases (RTKs) are a family of cell surface receptors that play critical roles in signal transduction from extracellular stimuli. Many of this family of kinases are overexpressed or mutated in human malignancies and thus became attractive drug target for cancer treatment. The signaling mediated by RTKs must be tightly regulated by interacting proteins including protein-tyrosine phosphatases and ubiquitin ligases. The suppressor of cytokine signaling (SOCS) family proteins are well known negative regulators of cytokine receptors signaling consisting of eight structurally similar proteins, SOCS1-7 and CIS. A key feature of this family of proteins is the presence of an SH2 domain and a SOCS box. Recent studies suggest that SOCS proteins also play a role in RTK signaling. Activation of RTK results in transcriptional activation of SOCS encoding genes. These proteins associate with RTKs through their SH2 domains and subsequently recruit the E3 ubiquitin machinery through the SOCS box, and thereby limit receptor stability by inducing ubiquitination. In a similar fashion SOCS proteins negatively regulate mitogenic signaling by RTKs. It is also evident that RTKs sometimes can bypass SOCS regulation and SOCS proteins can even potentiate RTKs-mediated mitogenic signaling. Thus apart from negative regulation of receptor signaling, SOCS proteins may also influence signaling in other ways.

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Section: Socs5mentioning

confidence: 99%

SOCS proteins in regulation of receptor tyrosine kinase signaling

Kazi

Kabir

Flores‐Morales

2014

Cell. Mol. Life Sci.

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“…4 The function of SOCS5 is not yet clear, but it is thought to act as a tumor suppressor and was shown previously to act as an inhibitor of janus kinase/signal transducer and activation of transcription pathways in endothelial cells. 13 Here, Loyer et al 4 show that inhibition of SOCS5 by siRNA increases monocyte chemoattractant protein-1 and interleukin-6 release without affecting KLF2, KLF4, and NOS3 levels, indicating that SOCS5 indeed directly protects against endothelial activation and inflammation. In which stages of atherosclerosis development the miR-92a-SOCS5 pathway plays its most prominent role still warrants further investigation.…”

Section: Circulation Researchmentioning

confidence: 88%

MiR-92a

Winther

Lutgens

2014

Circulation Research

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Editorial During life, our arteries with their 3 layers, numerous curvatures, branch points, and bifurcations, are continuously exposed to different flow and shear stress conditions. At branch points and bifurcations, especially oscillatory shear stress activates the endothelium, making these arterial sites prone to develop atherosclerosis.1,2 The subendothelial deposition and subsequent modification of lipids, such as low-density lipoprotein (LDL), further enhances this vascular inflammation. Along with endothelial activation, both the innate and adaptive immune system come into play, resulting in further recruitment of leukocytes and formation of atherosclerotic plaques. 1,2 Article, see p 434To keep the development of atherosclerosis under control, our arteries are subjected to a tight regulation to maintain their homeostasis. Regulatory RNAs, including micro-RNAs, are powerful post-transcriptional mediators that control vascular homeostasis, and their deregulation can result in aggravation of endothelial dysfunction and aggravation of vascular disease. Micro-RNAs can therefore be considered as potential novel therapeutics to treat cardiovascular disease. 3In this issue of Circulation Research, Loyer et al 4 performed an elegant screening to identify micro-RNAs affecting atherosclerosis, the so-called atheromiRs, in endothelial cells. The authors selected the atheromiRs in in vitro settings using human umbilical vein endothelial cells based on 2 criteria that are highly relevant for the pathogenesis of atherosclerosis: (1) miRs that exhibit a change in expression by exposure to oxidized LDL (oxLDL) under low shear stress and (2) miRs that are not affected by oxLDL exposure under high shear stress conditions. The miR that was most dysregulated and fulfilled these criteria was miR-92a, which was highly expressed in atherosclerosis-prone regions in normocholesterolemic ldlr −/− mice compared with atherosclerosis-resistant regions in these mice. This difference in miR-92a expression was further enhanced when the ldlr −/− mice were fed a diet to induce hypercholesterolemia. 4 Moreover, miR-92a seemed to be highly specific for the atherosclerotic endothelium: macrophages and smooth muscle cells that were exposed to oxLDL expressed miR-92a only at a low level. The authors unequivocally showed in vivo evidence for the importance of atheromiR-92a by treating ldlr −/− mice with an antagomir against miR-92a. Treated ldlr −/− mice did not only show a reduction in plaque area but also developed plaques that contained less T cells and macrophages and contained more fibrosis, 4 a phenotype that is reminiscent of a stable human atherosclerotic plaque.The findings of Loyer et al 4 are not unexpected. MiR-92a, which is part of the miR-17-92 cluster, has been proposed to be a therapeutic target for cardiovascular disease before. Several articles have found the miR-17-92 cluster to be correlated with regions of low shear stress. MiR-92a was found to be upregulated in endothelial cells by oscillatory flow. 5 In vivo, miR-92a was ...

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“…6 We also demonstrated that SOCS5 could bind all four JAK family members, although it was found to selectively inhibit only JAK1 and JAK2 autophosphorylation, and this function was dependent on the SOCS5 N-terminal region. 22 The conserved N-terminal region in SOCS5 (SOCS5 175-244 ) facilitates a direct interaction with the kinase domain of JAK and has therefore been designated the JAK interaction region (JIR). 22 The equilibrium dissociation constant (K D ) for the interaction of SOCS5 JIR with the kinase domain of JAK1 was found to be 0.5 µM.…”

Section: Introductionmentioning

confidence: 99%

“…22 The conserved N-terminal region in SOCS5 (SOCS5 175-244 ) facilitates a direct interaction with the kinase domain of JAK and has therefore been designated the JAK interaction region (JIR). 22 The equilibrium dissociation constant (K D ) for the interaction of SOCS5 JIR with the kinase domain of JAK1 was found to be 0.5 µM. 22 Deletion of the JIR impaired the ability of SOCS5 to inhibit IL-4 induced STAT6 activity, suggesting that this region was functionally important.…”

Section: Introductionmentioning

confidence: 99%

“…22 The equilibrium dissociation constant (K D ) for the interaction of SOCS5 JIR with the kinase domain of JAK1 was found to be 0.5 µM. 22 Deletion of the JIR impaired the ability of SOCS5 to inhibit IL-4 induced STAT6 activity, suggesting that this region was functionally important. 22 In this study, we characterize the conformation and dynamics of the JIR of mouse SOCS5 (mSOCS5 175-244 ) by solution NMR spectroscopy.…”

Section: Introductionmentioning

confidence: 99%

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Structure and Functional Characterization of the Conserved JAK Interaction Region in the Intrinsically Disordered N-Terminus of SOCS5

et al. 2015

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SOCS5 can negatively regulate both JAK/STAT and EGF-receptor pathways and has therefore been implicated in regulating both the immune response and tumorigenesis. Understanding the molecular basis for SOCS5 activity may reveal novel ways to target key components of these signaling pathways. The N-terminal region of SOCS5 coordinates critical protein interactions involved in inhibition of JAK/STAT signaling, and a conserved region within the N-terminus of SOCS5 mediates direct binding to the JAK kinase domain. Here we have characterized the solution conformation of this conserved JAK interaction region (JIR) within the largely disordered N-terminus of SOCS5. Using nuclear magnetic resonance (NMR) chemical shift analysis, relaxation measurements, and NOE analysis, we demonstrate the presence of preformed structural elements in the JIR of mouse SOCS5 (mSOCS5175–244), consisting of an α-helix encompassing residues 224–233, preceded by a turn and an extended structure. We have identified a phosphorylation site (Ser211) within the JIR of mSOCS5 and have investigated the role of phosphorylation in modulating JAK binding using site-directed mutagenesis.

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Suppressor of Cytokine Signaling (SOCS) 5 Utilises Distinct Domains for Regulation of JAK1 and Interaction with the Adaptor Protein Shc-1

Cited by 45 publications

References 64 publications

SOCS proteins in regulation of receptor tyrosine kinase signaling

SOCS proteins in regulation of receptor tyrosine kinase signaling

MiR-92a

Structure and Functional Characterization of the Conserved JAK Interaction Region in the Intrinsically Disordered N-Terminus of SOCS5

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