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Src family kinases interfere with dimerization of STAT5A through a phosphotyrosine-SH2 domain interaction
BACKGROUND: Chronic myeloid leukemia (CML) is driven by the expression of the BCR-ABL oncoprotein. STAT5 is a BCR-ABL substrate and persistently activated by tyrosine phosphorylation in CML cells. Activated STAT5 (pSTAT5) drives proliferation and survival of leukemic cells and contributes to initial...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4350284/ https://www.ncbi.nlm.nih.gov/pubmed/25885255 http://dx.doi.org/10.1186/s12964-014-0081-7 |
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author | Fahrenkamp, Dirk de Leur, Hildegard Schmitz-Van Küster, Andrea Chatain, Nicolas Müller-Newen, Gerhard |
author_facet | Fahrenkamp, Dirk de Leur, Hildegard Schmitz-Van Küster, Andrea Chatain, Nicolas Müller-Newen, Gerhard |
author_sort | Fahrenkamp, Dirk |
collection | PubMed |
description | BACKGROUND: Chronic myeloid leukemia (CML) is driven by the expression of the BCR-ABL oncoprotein. STAT5 is a BCR-ABL substrate and persistently activated by tyrosine phosphorylation in CML cells. Activated STAT5 (pSTAT5) drives proliferation and survival of leukemic cells and contributes to initial transformation and maintenance of the disease. In cytokine-induced STAT5 signaling, phosphorylation of STAT5A on Y694 leads to nuclear accumulation of the transcription factor, followed by DNA-binding and gene induction. However, Src-family kinases (SFK) mediate cytoplasmic retention of pSTAT5A leading to attenuated target gene expression and colony formation in CML cells. RESULTS: In this study we show that autophosphorylation of Y416 in the highly conserved activation loop of SFK generates a potent recruitment site for the SH2 domain of STAT5A. Binding of the SH2 domain to the activation loop is required for STAT5A(Y694) phosphorylation by SFK, but at the same time promotes the persistent cytoplasmic localization of the transcription factor as found in BCR-ABL(+) leukemia. As a consequence of the complex formation between tyrosine-phosphorylated SFK and the SH2 domain of STAT5A, the dimerization of STAT5A is impaired. We further demonstrate that constitutively active STAT5A(S710F) escapes from SFK-mediated cytoplasmic retention by enhancing STAT5A dimer stability. CONCLUSION: Our results reveal important structural aspects of cytoplasmic pSTAT5A found in myeloid leukemias and will contribute to the understanding of STAT5A mediated cytoplasmic signaling. |
format | Online Article Text |
id | pubmed-4350284 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-43502842015-03-06 Src family kinases interfere with dimerization of STAT5A through a phosphotyrosine-SH2 domain interaction Fahrenkamp, Dirk de Leur, Hildegard Schmitz-Van Küster, Andrea Chatain, Nicolas Müller-Newen, Gerhard Cell Commun Signal Research BACKGROUND: Chronic myeloid leukemia (CML) is driven by the expression of the BCR-ABL oncoprotein. STAT5 is a BCR-ABL substrate and persistently activated by tyrosine phosphorylation in CML cells. Activated STAT5 (pSTAT5) drives proliferation and survival of leukemic cells and contributes to initial transformation and maintenance of the disease. In cytokine-induced STAT5 signaling, phosphorylation of STAT5A on Y694 leads to nuclear accumulation of the transcription factor, followed by DNA-binding and gene induction. However, Src-family kinases (SFK) mediate cytoplasmic retention of pSTAT5A leading to attenuated target gene expression and colony formation in CML cells. RESULTS: In this study we show that autophosphorylation of Y416 in the highly conserved activation loop of SFK generates a potent recruitment site for the SH2 domain of STAT5A. Binding of the SH2 domain to the activation loop is required for STAT5A(Y694) phosphorylation by SFK, but at the same time promotes the persistent cytoplasmic localization of the transcription factor as found in BCR-ABL(+) leukemia. As a consequence of the complex formation between tyrosine-phosphorylated SFK and the SH2 domain of STAT5A, the dimerization of STAT5A is impaired. We further demonstrate that constitutively active STAT5A(S710F) escapes from SFK-mediated cytoplasmic retention by enhancing STAT5A dimer stability. CONCLUSION: Our results reveal important structural aspects of cytoplasmic pSTAT5A found in myeloid leukemias and will contribute to the understanding of STAT5A mediated cytoplasmic signaling. BioMed Central 2015-02-15 /pmc/articles/PMC4350284/ /pubmed/25885255 http://dx.doi.org/10.1186/s12964-014-0081-7 Text en © Fahrenkamp et al.; licensee BioMed Central. 2015 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Fahrenkamp, Dirk de Leur, Hildegard Schmitz-Van Küster, Andrea Chatain, Nicolas Müller-Newen, Gerhard Src family kinases interfere with dimerization of STAT5A through a phosphotyrosine-SH2 domain interaction |
title | Src family kinases interfere with dimerization of STAT5A through a phosphotyrosine-SH2 domain interaction |
title_full | Src family kinases interfere with dimerization of STAT5A through a phosphotyrosine-SH2 domain interaction |
title_fullStr | Src family kinases interfere with dimerization of STAT5A through a phosphotyrosine-SH2 domain interaction |
title_full_unstemmed | Src family kinases interfere with dimerization of STAT5A through a phosphotyrosine-SH2 domain interaction |
title_short | Src family kinases interfere with dimerization of STAT5A through a phosphotyrosine-SH2 domain interaction |
title_sort | src family kinases interfere with dimerization of stat5a through a phosphotyrosine-sh2 domain interaction |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4350284/ https://www.ncbi.nlm.nih.gov/pubmed/25885255 http://dx.doi.org/10.1186/s12964-014-0081-7 |
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