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Department of Surgery and Comprehensive Cancer Center, University of California, San Francisco, CA 94115
The type 1 TNFR (TNFR1) contains a death domain through which it interacts with other death-domain proteins to promote cellular responses. However, signaling through death-domain proteins does not explain how TNFR1 induces the tyrosine phosphorylation of intracellular proteins, which are important to cellular responses induced by TNFR1. In this study, we show that TNFR1 associates with Jak2, c-Src, and PI3K in various cell types. Jak2 and c-Src constitutively associate with and are constitutively active in the TNFR1 complex. Stimulation with TNF induces a time-dependent change in the level of Jak2, c-Src, and PI3K associated with TNFR1. The tyrosine kinase activity of the complex varies with the level of tyrosine kinase associated with TNFR1. TNFR1/c-Src plays a role in activating Akt, but not JNK or p38 MAPK, whereas TNFR1/Jak2 plays a role in activating p38 MAPK, JNK, and Akt. TNFR1/c-Src, but not TNFR1/Jak2, plays an obligate role in the activation of NF-
B by TNF, whereas TNFR1/Jak2, but not TNFR1/c-Src, plays an obligate role in the activation of STAT3. Activation of TNFR1 increased the expression of vascular endothelial growth factor, p21WAF1/CIP1, and manganese superoxide dismutase in MCF7 breast cancer cells, and increased the expression of CCl2/MCP-1 and IL-1β in THP-1 macrophages. Inhibitors of Jak2 and c-Src impaired the induction of each of these target proteins. These observations show that TNFR1 associates with and uses nonreceptor tyrosine kinases to engage signaling pathways, activate transcription factors, and modulate gene expression in cells.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grant CA67891.
2 Address correspondence and reprint requests to Dr. Roxana Pincheira or Dr. David B. Donner, Department of Surgery and Comprehensive Cancer Center, University of California, 1600 Divisadero Street, San Francisco, CA 94115. E-mail addresses: pincheirar{at}surgery.ucsf.edu and donnerd{at}surgery.ucsf.edu
3 Abbreviations used in this paper: TNFR1, type 1 TNFR; TRADD, TNFR-associated death-domain protein; RIP, receptor-interacting protein; TRAF, TNFR-associated factor; VEGF, vascular endothelial growth factor; MnSOD, manganese superoxide dismutase; IKK, IB kinase.
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