title: Suppressor of cytokine signaling 3 inhibits breast tumor kinase activation of STAT3.
abstract: Breast tumor kinase (Brk) was originally isolated from a human metastatic breast tumor, but also is found expressed in other epithelial tumors and in a subset of normal epithelia. Brk is a tyrosine kinase and its expression in breast carcinoma has been linked to tumor progression. The signal transducer and activator of transcription 3 (STAT3) is one of the substrate targets of Brk, and elevated tyrosine phosphorylation of STAT3 is known to contribute to oncogenesis. Conventional activation of STAT3 occurs in response to cytokine stimulation of Janus tyrosine kinases (JAK). One of the negative regulators discovered in cytokine signaling of the JAK-STAT pathway is the suppressor of cytokine signaling 3 (SOCS3). In this report we describe the finding that SOCS3 can also inhibit the unconventional target, Brk. Investigation of the mechanism by which SOCS3 inhibits Brk reveals the SOCS3 protein binds to Brk primarily via its SH2 domain, and its main inhibitory effect is mediated by the SOCS3 kinase inhibitory region (KIR). SOCS3 has only a modest effect on promoting Brk degradation, and this requires the C-terminal SOCS box domain. SOCS3 is the only known inhibitor of Brk, and knowledge of the mechanisms by which SOCS3 inhibits Brk may lead to methods that block Brk in cancer progression.
authors.affiliation: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York 11794, USA.
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Gao
authors.forename: Velasco
authors.initials: V
authors.lastname: Cimica
authors.forename: Nancy C
authors.initials: NC
authors.lastname: Reich
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004789:Enzyme Activation / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D018909:src Homology Domains
chemical_list: D009363:Neoplasm Proteins; C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D011505:Protein-Tyrosine Kinases; C088375:PTK6 protein, human