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J. Biol. Chem., Vol. 281, Issue 3, 1371-1380, January 20, 2006

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The Tyrosine Kinase Syk Regulates TPL2 Activation Signals^*

Aristides G. Eliopoulos1, Santasabuj Das¶, and Philip N. Tsichlis¶

From the Laboratory of Molecular and Cellular Biology, Division of Basic Sciences, the University of Crete Medical School, Heraklion 71003, Crete, Greece, Cancer Research UK Institute for Cancer Studies, the University of Birmingham Medical School, Birmingham B15 2TA, United Kingdom, and ^¶Molecular Oncology Research Institute, Tufts-New England Medical Center, Boston, Massachusetts 02111

Tpl2/Cot is a serine/threonine kinase that plays a key physiological role in the regulation of immune responses to pro-inflammatory stimuli, including tumor necrosis factor- (TNF-). TNF- stimulates the JNK, ERK, and p38 mitogen-activated protein kinases and the NF-B pathway by recruiting RIP1 and TRAF2 to the TNF receptor 1. Here we showed that Tpl2 activation by TNF- signals depends on the integrity of the Tpl2-interacting proteins RIP1 and TRAF2, which are required for the engagement of the ERK mitogen-activated protein kinase pathway. However, neither RIP1 nor TRAF2 overexpression was sufficient to activate Tpl2 and ERK. We also showed that Tpl2 activation by TNF- depends on a tyrosine kinase activity that is detected in TNF--stimulated cells. Based on both genetic and biochemical evidence, we concluded that in a variety of cell types, Syk is the tyrosine kinase that plays an important role in the activation of Tpl2 upstream of ERK. These data therefore dissect the TNF receptor 1 proximal events that regulate Tpl2 and ERK and highlight a role for RIP1, TRAF2, and Syk in this pathway.

Received for publication, June 22, 2005 , and in revised form, October 21, 2005.

^* This work was supported by a Medical Research Council (UK) Career Development award (to A. G. E.) and National Institutes of Health Grant RO1 CA38047 (to P. N. T.). 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 To whom correspondence should be addressed. Tel.: 30-2810-394-565; Fax: 30-2810-394-632; E-mail: eliopag{at}med.uoc.gr.

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