Suppressor of Cytokine Signaling (SOCS) 5 utilises distinct domains for regulation of JAK1 and interaction with the adaptor protein Shc-1
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 int...
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| creator | Linossi, Edmond M Chandrashekaran, Indu R Kolesnik, Tatiana B Murphy, James M Webb, Andrew I Willson, Tracy A Kedzierski, Lukasz Bullock, Alex N Babon, Jeffrey J Norton, Raymond S Nicola, Nicos A Nicholson, Sandra E |
| description | 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. |
| doi_str_mv | 10.1371/journal.pone.0070536 |
| format | Article |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0070536</identifier><identifier>PMID: 23990909</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adapter proteins ; Animals ; Binding Sites ; Biology ; Cytokines ; Cytokines - metabolism ; Epidermal growth factor ; Epidermal growth factors ; Genetic Vectors ; HEK293 Cells ; Humans ; Intercellular Signaling Peptides and Proteins - metabolism ; Janus kinase ; Janus Kinase 1 - metabolism ; Janus kinase 2 ; Janus Kinase 2 - metabolism ; Janus Kinase 3 - metabolism ; Kinases ; Lymphocytes ; Medical research ; Mice ; Mutation ; N-Terminus ; Pharmaceutical sciences ; Phosphopeptides - chemistry ; Phosphorylation ; Protein Structure, Tertiary ; Recombinant Proteins - chemistry ; Rodents ; Sequences ; Shc protein ; Shc Signaling Adaptor Proteins - metabolism ; Signal Transduction ; Signaling ; SOCS-1 protein ; Src Homology 2 Domain-Containing, Transforming Protein 1 ; src Homology Domains ; Substrate Specificity ; Substrates ; Suppressor of Cytokine Signaling Proteins - metabolism ; Surface Plasmon Resonance ; Tumors ; TYK2 Kinase - metabolism ; Tyk2 protein</subject><ispartof>PloS one, 2013-08, Vol.8 (8), p.e70536-e70536</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Linossi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Linossi et al 2013 Linossi et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c593t-af48aa24a8b5654f44082983e59a4bc45f0ad9cdd29435e769fb3ea7922eb013</citedby><cites>FETCH-LOGICAL-c593t-af48aa24a8b5654f44082983e59a4bc45f0ad9cdd29435e769fb3ea7922eb013</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3749136/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3749136/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79569,79570</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23990909$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Linossi, Edmond M</creatorcontrib><creatorcontrib>Chandrashekaran, Indu R</creatorcontrib><creatorcontrib>Kolesnik, Tatiana B</creatorcontrib><creatorcontrib>Murphy, James M</creatorcontrib><creatorcontrib>Webb, Andrew I</creatorcontrib><creatorcontrib>Willson, Tracy A</creatorcontrib><creatorcontrib>Kedzierski, Lukasz</creatorcontrib><creatorcontrib>Bullock, Alex N</creatorcontrib><creatorcontrib>Babon, Jeffrey J</creatorcontrib><creatorcontrib>Norton, Raymond S</creatorcontrib><creatorcontrib>Nicola, Nicos A</creatorcontrib><creatorcontrib>Nicholson, Sandra E</creatorcontrib><title>Suppressor of Cytokine Signaling (SOCS) 5 utilises distinct domains for regulation of JAK1 and interaction with the adaptor protein Shc-1</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>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. 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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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23990909</pmid><doi>10.1371/journal.pone.0070536</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2013-08, Vol.8 (8), p.e70536-e70536 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1430785194 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Adapter proteins Animals Binding Sites Biology Cytokines Cytokines - metabolism Epidermal growth factor Epidermal growth factors Genetic Vectors HEK293 Cells Humans Intercellular Signaling Peptides and Proteins - metabolism Janus kinase Janus Kinase 1 - metabolism Janus kinase 2 Janus Kinase 2 - metabolism Janus Kinase 3 - metabolism Kinases Lymphocytes Medical research Mice Mutation N-Terminus Pharmaceutical sciences Phosphopeptides - chemistry Phosphorylation Protein Structure, Tertiary Recombinant Proteins - chemistry Rodents Sequences Shc protein Shc Signaling Adaptor Proteins - metabolism Signal Transduction Signaling SOCS-1 protein Src Homology 2 Domain-Containing, Transforming Protein 1 src Homology Domains Substrate Specificity Substrates Suppressor of Cytokine Signaling Proteins - metabolism Surface Plasmon Resonance Tumors TYK2 Kinase - metabolism Tyk2 protein |
| title | Suppressor of Cytokine Signaling (SOCS) 5 utilises distinct domains for regulation of JAK1 and interaction with the adaptor protein Shc-1 |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-13T23%3A20%3A05IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Suppressor%20of%20Cytokine%20Signaling%20(SOCS)%205%20utilises%20distinct%20domains%20for%20regulation%20of%20JAK1%20and%20interaction%20with%20the%20adaptor%20protein%20Shc-1&rft.jtitle=PloS%20one&rft.au=Linossi,%20Edmond%20M&rft.date=2013-08-21&rft.volume=8&rft.issue=8&rft.spage=e70536&rft.epage=e70536&rft.pages=e70536-e70536&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0070536&rft_dat=%3Cgale_plos_%3EA478186025%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1430785194&rft_id=info:pmid/23990909&rft_galeid=A478186025&rft_doaj_id=oai_doaj_org_article_1bd4c33ee3a949f28850bca64c3e1c57&rfr_iscdi=true |