The tyrosine kinase Syk regulates TPL2 activation signals.

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-kappaB 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.
Mesh Terms:
Animals, Breast Neoplasms, Cell Line, Cell Line, Tumor, Female, Humans, Intracellular Signaling Peptides and Proteins, Jurkat Cells, MAP Kinase Kinase Kinases, MAP Kinase Signaling System, Mice, Mice, Knockout, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, RNA, Small Interfering, Recombinant Proteins, Transfection, Tumor Necrosis Factor-alpha, ZAP-70 Protein-Tyrosine Kinase
J. Biol. Chem.
Date: Jan. 20, 2006
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