Abstract
TRAF2 has an important function in mediating the TNF-R signaling pathway toward activation of NF-κB and JNKs. Here we reveal a novel function of TRAF2 in the epidermal growth factor (EGF) signaling pathway. Knockdown of TRAF2 blocked EGF-induced AP-1 activity and anchorage- independent cell transformation. Notably, we showed that EGF induces ribosomal S6 kinase 2 (RSK2) ubiquitination, and knocking down TRAF2 suppresses ubiquitination of RSK2 induced by EGF. We also found that TRAF2 affects RSK2 activity through RSK2 ubiquitination. RSK2 plays a critical role in AP-1 activity mediated through CREB and c-Fos, which regulates anchorage-independent cell transformation. In addition, TRAF2 is overexpressed in colon cancer and required for colon cancer development, suggesting that TRAF2 might be a potential molecular target for cancer prevention and treatment.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line, Tumor
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Cell Proliferation
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Cell Transformation, Neoplastic / metabolism
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Colorectal Neoplasms / metabolism
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Colorectal Neoplasms / pathology
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Cyclic AMP Response Element-Binding Protein / metabolism*
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Epidermal Growth Factor / physiology*
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Female
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Gene Knockdown Techniques
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Humans
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Mice
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Mice, Nude
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Neoplasm Transplantation
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Polyubiquitin / metabolism
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Protein Binding
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Protein Processing, Post-Translational
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Proto-Oncogene Proteins c-fos / metabolism*
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Ribosomal Protein S6 Kinases, 90-kDa / metabolism*
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Signal Transduction
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TNF Receptor-Associated Factor 2 / genetics
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TNF Receptor-Associated Factor 2 / metabolism*
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Transcription Factor AP-1 / metabolism
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Transcription, Genetic
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Tumor Burden
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Ubiquitination
Substances
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Cyclic AMP Response Element-Binding Protein
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Proto-Oncogene Proteins c-fos
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TNF Receptor-Associated Factor 2
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Transcription Factor AP-1
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Polyubiquitin
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Epidermal Growth Factor
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Ribosomal Protein S6 Kinases, 90-kDa
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ribosomal protein S6 kinase, 90kDa, polypeptide 3