title: Suppressor of Cytokine Signaling (SOCS) 5 utilises distinct domains for regulation of JAK1 and interaction with the adaptor protein Shc-1.
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.
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia ; The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Edmond M
authors.initials: EM
authors.lastname: Linossi
authors.forename: Indu R
authors.initials: IR
authors.lastname: Chandrashekaran
authors.forename: Tatiana B
authors.initials: TB
authors.lastname: Kolesnik
authors.forename: James M
authors.initials: JM
authors.lastname: Murphy
authors.forename: Andrew I
authors.initials: AI
authors.lastname: Webb
authors.forename: Tracy A
authors.initials: TA
authors.lastname: Willson
authors.forename: Lukasz
authors.initials: L
authors.lastname: Kedzierski
authors.forename: Alex N
authors.initials: AN
authors.lastname: Bullock
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Babon
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Norton
authors.forename: Nicos A
authors.initials: NA
authors.lastname: Nicola
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Nicholson
mesh_terms: D000818:Animals; D001665:Binding Sites; D016207:Cytokines / Q000378:metabolism; D005822:Genetic Vectors; D057809:HEK293 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D053613:Janus Kinase 1 / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000378:metabolism; D053616:Janus Kinase 3 / Q000378:metabolism; D051379:Mice; D010748:Phosphopeptides / Q000737:chemistry; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry; D055765:Shc Signaling Adaptor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013379:Substrate Specificity; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D020349:Surface Plasmon Resonance; D053634:TYK2 Kinase / Q000378:metabolism; D018909:src Homology Domains
chemical_list: D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D010748:Phosphopeptides; D011994:Recombinant Proteins; C528024:SHC1 protein, human; C408990:SOCS5 protein, human; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D050826:Suppressor of Cytokine Signaling Proteins; C507904:JAK1 protein, human; C507933:JAK3 protein, human; C507905:Jak1 protein, mouse; C507926:Jak2 protein, mouse; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053616:Janus Kinase 3; D053634:TYK2 Kinase; C499356:Tyk2 protein, mouse