Identification of STAT3 as a specific substrate of breast tumor kinase

• Published in: Oncogene Vol. 25; no. 35; pp. 4904 - 4912
• Main Authors: LIU, L, GAO, Y, QIU, H, MILLER, W. T, POLI, V, REICH, N. C
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 10-08-2006; Nature Publishing Group
• Subjects: Animals; Biological and medical sciences; Breast cancer; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cercopithecus aethiops; COS Cells; Cytokine receptors; Cytokines; Enzymes; Fundamental and applied biological sciences. Psychology; Gynecology. Andrology. Obstetrics; HeLa Cells; Humans; Mammary gland diseases; Medical sciences; Molecular and cellular biology; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - physiology; Phosphorylation; Protein-tyrosine kinase receptors; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - physiology; Signal transduction; Stat3 protein; STAT3 Transcription Factor - metabolism; Substrate Specificity; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins - physiology; Transcription activation; Tumorigenesis; Tumors; Tyrosine - metabolism; Tyrosine; Mammary gland diseases; Signal transduction; Phosphorylation; Enzyme; Kinase; Transferases; Breast tumor; Identification; tyrosine phosphorylation; Transcription factor; Carcinogenesis
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1209501

Breast tumor kinase (Brk) is a non-receptor tyrosine kinase distantly related to the Src family kinase. It is expressed in more than 60% of breast tumors, but the biological role of this kinase remains to be determined. Only a limited number of substates have been identified for Brk, and the link of Brk to tumorigenesis remains largely unknown. In this study, we provide evidence that the signal transducer and activator of transcription 3, STAT3, is a physiological target of Brk. Activation of STAT3 previously has been linked to oncogenesis, and results in this study demonstrate that STAT3 is tyrosine phosphorylated and transcriptionally activated in cells expressing endogenous Brk. Signal transducer and activator of transcription 3 is specifically targeted since other STAT members are not responsive to Brk expression. Signal transducer and activator of transcription 3 activation requires the catalytic activity of Brk, and expression of both STAT3 and Brk stimulate cellular proliferation. In addition, we have identified a negative regulator of Brk, the suppressor of cytokine signaling, SOCS3. The SOCS3 protein is known to block signaling mediated by cytokine receptors, and here we find that SOCS3 is able to repress the activity of the Brk non-receptor tyrosine kinase.