Requirement for Ras/Rac1-Mediated p38 and c-Jun N-Terminal Kinase Signaling in Stat3 Transcriptional Activity Induced by the Src Oncoprotein
| Autor: | Jie Wu, Madhavi Sekharam, Yi Zhang, Julie Y. Djeu, David A. Frank, Tammy Bowman, Jalila Adnane, James Turkson, Said M. Sebti, Richard Jove, Lawrence B. Holzman |
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| Rok vydání: | 1999 |
| Předmět: |
STAT3 Transcription Factor
rac1 GTP-Binding Protein Saccharomyces cerevisiae Proteins Transcription Genetic MAP Kinase Signaling System Biology SH2 domain SH3 domain Oncogene Protein pp60(v-src) MAP2K7 Mice Serine Animals Phosphorylation Cell Growth and Development Molecular Biology Serine/threonine-specific protein kinase Tyrosine-protein kinase CSK Models Genetic MAP kinase kinase kinase JNK Mitogen-Activated Protein Kinases 3T3 Cells Cell Biology Molecular biology Cell biology DNA-Binding Proteins Gene Expression Regulation Neoplastic Cell Transformation Neoplastic Trans-Activators Mitogen-Activated Protein Kinases Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | Molecular and Cellular Biology. 19:7519-7528 |
| ISSN: | 1098-5549 |
| DOI: | 10.1128/mcb.19.11.7519 |
| Popis: | Signal transducers and activators of transcription (STATs) are transcription factors that mediate normal biologic responses to cytokines and growth factors. However, abnormal activation of certain STAT family members, including Stat3, is increasingly associated with oncogenesis. In fibroblasts expressing the Src oncoprotein, activation of Stat3 induces specific gene expression and is required for cell transformation. Although the Src tyrosine kinase induces constitutive Stat3 phosphorylation on tyrosine, activation of Stat3-mediated gene regulation requires both tyrosine and serine phosphorylation of Stat3. We investigated the signaling pathways underlying the constitutive Stat3 activation in Src oncogenesis. Expression of Ras or Rac1 dominant negative protein blocks Stat3-mediated gene regulation induced by Src in a manner consistent with dependence on p38 and c-Jun N-terminal kinase (JNK). Both of these serine/threonine kinases and Stat3 serine phosphorylation are constitutively induced in Src-transformed fibroblasts. Furthermore, inhibition of p38 and JNK activities suppresses constitutive Stat3 serine phosphorylation and Stat3-mediated gene regulation. In vitro kinase assays with purified full-length Stat3 as the substrate show that both JNK and p38 can phosphorylate Stat3 on serine. Moreover, inhibition of p38 activity and thus of Stat3 serine phosphorylation results in suppression of transformation by v-Src but not v-Ras, consistent with a requirement for Stat3 serine phosphorylation in Src transformation. Our results demonstrate that Ras- and Rac1-mediated p38 and JNK signals are required for Stat3 transcriptional activity induced by the Src oncoprotein. These findings delineate a network of tyrosine and serine/threonine kinase signaling pathways that converge on Stat3 in the context of oncogenesis. |
| Databáze: | OpenAIRE |
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