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The tyrosine kinase Syk regulates TPL2 activation signals

, : The tyrosine kinase Syk regulates TPL2 activation signals. Journal of Biological Chemistry 281(3): 1371-1380

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-[alpha] (TNF-[alpha]). TNF-[alpha] stimulates the JNK, ERK, and p38 mitogen-activated protein kinases and the NF-[kappa]B pathway by recruiting RIP1 and TRAF2 to the TNF receptor 1. Here we showed that Tpl2 activation by TNF-[alpha] 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-[alpha] depends on a tyrosine kinase activity that is detected in TNF-[alpha]-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.


PMID: 16291755

DOI: 10.1074/jbc.M506790200

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