We are analyzing https://link.springer.com/article/10.1186/bcr1794.

Title:
Signal transducer and activator of transcription 5b: a new target of breast tumor kinase/protein tyrosine kinase 6 | Breast Cancer Research
Description:
Introduction Signal transducers and activators of transcription (STATs) are mediators of cytokine and growth factor signaling. In recent years, STAT5b has emerged as a key regulator of tumorigenesis. STAT5b phosphorylation and activation is mediated by several kinases known to be overexpressed in breast cancer, such as epidermal growth factor receptor, HER2, and c-Src. Breast tumor kinase (Brk), also known as protein tyrosine kinase 6, is a nonreceptor tyrosine kinase expressed in more than 60% of breast cancers. Only a few substrates of the Brk tyrosine kinase have been identified, the most recent being STAT3. In the present article we investigate the potential role of Brk in the phosphorylation and activation STAT5b. Methods To determine whether Brk can phosphorylate STAT5b, transient transfection and in vitro kinase assays were performed. Luciferase reporter assays were used to measure Brk-induced STAT5b transcriptional activity. siRNA technology was utilized to investigate the biological significance of Brk-induced activation of STAT5b in breast cancer cell models. Results Phosphospecific antibodies, mutational analysis, and in vitro kinase assays demonstrated that Brk specifically mediated STAT5b phosphorylation at the activating tyrosine, Y699. Transient transfection of Brk into the Brk-negative BT-549 breast cancer cell line enhanced STAT5b transcriptional activity, as measured by a STAT5-specific luciferase reporter. Furthermore, overexpression of kinase active c-Src enhanced Brk-induced STAT5b transcriptional activity. In Brk-positive breast cancer cell lines BT-20 and SKBr3, knockdown of Brk protein or of STAT5b protein using siRNA methodology resulted in a decrease in DNA synthesis. Knockdown of Brk and STAT5b together did not further decrease DNA synthesis compared with each alone, suggesting that Brk and STAT5b converge on the same pathway, ultimately leading to cellular proliferation. Conclusion Our studies demonstrate that Brk phosphorylates STAT5b on Y699, leading to increased STAT5b transcriptional activity. Furthermore, analysis of DNA synthesis suggests that STAT5b and Brk are converging upon the same proproliferative signaling pathway in breast cancer cells. We propose that Brk, like other tyrosine kinases, signals downstream to STAT5b to mediate proliferation of breast cancer cells. These results further establish STAT5b as well as Brk as potential targets for breast cancer therapy.
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Keywords {🔍}

brk, statb, breast, cancer, cells, kinase, tyrosine, activity, cell, article, stat, csrc, pubmed, phosphorylation, google, scholar, cas, expression, figure, transcriptional, protein, tumor, kinases, growth, lines, activation, knockdown, signal, usa, prc, transcription, dna, synthesis, stata, role, luciferase, antibody, proliferation, transfected, analyzed, factor, receptor, expressed, performed, line, mediate, authors, mef, immunoblotting, biol,

Topics {✒️}

1 mm isopropyl-beta-d-thiogalactopyranoside estrogen-receptor-positive t47d cells estrogen-receptor-negative bt-20 cells epidermal growth factor-induced mda-mb-468 cell line c-src-preferred synthetic peptide article download pdf regulates heregulin-induced activation antiphospho-y699 stat5b-specific antibody epidermal growth factor erbb receptor-induced activation receptor protein-tyrosine kinase monoclonal anti-β-actin antibody specific phospho-y694/y699 stat5a/ egf signalling full size image c-src kinase activity kinase active c-src kinase-inactive brk mutant growth factor signaling antiphospho-y699-specific antibody anti-brdu-alexa-fluor 594 growth factor binding cell line expressed kinase inactive c-src kinase-inactive c-src decreased tumor growth breast tumor kinase stat5-specific luciferase reporter estrogen receptor status squamous cell carcinoma cell lines express growth factor signals receptor tyrosine kinase insulin receptor full access phospho-y699 stat5b antibody growth hormone signaling breast tumor-derived human ptk6 gene polyclonal anti-brk antibodies promotes cell migration human breast carcinomas breast tumor cells methods cell lines dominant-negative constructs metastatic breast cancer cell line nat rev cancer stat5b transcriptional activity

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         headline:Signal transducer and activator of transcription 5b: a new target of breast tumor kinase/protein tyrosine kinase 6
         description:Signal transducers and activators of transcription (STATs) are mediators of cytokine and growth factor signaling. In recent years, STAT5b has emerged as a key regulator of tumorigenesis. STAT5b phosphorylation and activation is mediated by several kinases known to be overexpressed in breast cancer, such as epidermal growth factor receptor, HER2, and c-Src. Breast tumor kinase (Brk), also known as protein tyrosine kinase 6, is a nonreceptor tyrosine kinase expressed in more than 60% of breast cancers. Only a few substrates of the Brk tyrosine kinase have been identified, the most recent being STAT3. In the present article we investigate the potential role of Brk in the phosphorylation and activation STAT5b. To determine whether Brk can phosphorylate STAT5b, transient transfection and in vitro kinase assays were performed. Luciferase reporter assays were used to measure Brk-induced STAT5b transcriptional activity. siRNA technology was utilized to investigate the biological significance of Brk-induced activation of STAT5b in breast cancer cell models. Phosphospecific antibodies, mutational analysis, and in vitro kinase assays demonstrated that Brk specifically mediated STAT5b phosphorylation at the activating tyrosine, Y699. Transient transfection of Brk into the Brk-negative BT-549 breast cancer cell line enhanced STAT5b transcriptional activity, as measured by a STAT5-specific luciferase reporter. Furthermore, overexpression of kinase active c-Src enhanced Brk-induced STAT5b transcriptional activity. In Brk-positive breast cancer cell lines BT-20 and SKBr3, knockdown of Brk protein or of STAT5b protein using siRNA methodology resulted in a decrease in DNA synthesis. Knockdown of Brk and STAT5b together did not further decrease DNA synthesis compared with each alone, suggesting that Brk and STAT5b converge on the same pathway, ultimately leading to cellular proliferation. Our studies demonstrate that Brk phosphorylates STAT5b on Y699, leading to increased STAT5b transcriptional activity. Furthermore, analysis of DNA synthesis suggests that STAT5b and Brk are converging upon the same proproliferative signaling pathway in breast cancer cells. We propose that Brk, like other tyrosine kinases, signals downstream to STAT5b to mediate proliferation of breast cancer cells. These results further establish STAT5b as well as Brk as potential targets for breast cancer therapy.
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         Breast Cancer Cell Line
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         Oncology
         Surgical Oncology
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