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Suppressor of Cytokine Signaling (SOCS)5 is thought to act as a tumour suppressor through negative regulation of JAK/STAT and epidermal growth factor (EGF) signaling. However, the mechanism/s by which SOCS5 acts on these two distinct pathways is unclear. We show for the first time that SOCS5 can interact directly with JAK via a unique, conserved region in its N-terminus, which we have termed the JAK interaction region (JIR). Co-expression of SOCS5 was able to specifically reduce JAK1 and JAK2 (but not JAK3 or TYK2) autophosphorylation and this function required both the conserved JIR and additional sequences within the long SOCS5 N-terminal region. We further demonstrate that SOCS5 can directly inhibit JAK1 kinase activity, although its mechanism of action appears distinct from that of SOCS1 and SOCS3. In addition, we identify phosphoTyr317 in Shc-1 as a high-affinity substrate for the SOCS5-SH2 domain and suggest that SOCS5 may negatively regulate EGF and growth factor-driven Shc-1 signaling by binding to this site. These findings suggest that different domains in SOCS5 contribute to two distinct mechanisms for regulation of cytokine and growth factor signaling.

Original publication

DOI

10.1371/journal.pone.0070536

Type

Journal article

Journal

PLoS One

Publication Date

2013

Volume

8

Keywords

Animals, Binding Sites, Cytokines, Genetic Vectors, HEK293 Cells, Humans, Intercellular Signaling Peptides and Proteins, Janus Kinase 1, Janus Kinase 2, Janus Kinase 3, Mice, Phosphopeptides, Phosphorylation, Protein Structure, Tertiary, Recombinant Proteins, Shc Signaling Adaptor Proteins, Signal Transduction, Src Homology 2 Domain-Containing, Transforming Protein 1, Substrate Specificity, Suppressor of Cytokine Signaling Proteins, Surface Plasmon Resonance, TYK2 Kinase, src Homology Domains