Suppressor of Cytokine Signaling (SOCS) 5 utilises distinct domains for regulation of JAK1 and interaction with the adaptor protein Shc-1.
- Author(s)
- Linossi, EM; Chandrashekaran, IR; Kolesnik, TB; Murphy, JM; Webb, AI; Willson, TA; Kedzierski, L; Bullock, AN; Babon, JJ; Norton, RS; Nicola, NA; Nicholson, SE;
- Details
- Publication Year 2013,Volume 8,Issue #8,Page e70536
- Journal Title
- PLoS One
- Publication Type
- Journal Article
- Abstract
- 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.
- Publisher
- Public Library of Science
- Keywords
- Complementary DNA ; Immunoprecipitation ; Kinase inhibitors ; Mutation ; Phosphorylation ; Protein expression ; 293T cells ; Binding analysis
- Research Division(s)
- Cancer And Haematology; Inflammation; Structural Biology; Systems Biology And Personalised Medicine; Molecular Medicine
- Link To PubMed Central Version
- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3749136/
- Publisher's Version
- https://doi.org/10.1371/journal.pone.0070536
- Open Access at Publisher's Site
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- Copyright: © 2013 Linossi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Creation Date: 2013-01-01 12:00:00