Selective regulation of tumor necrosis factor-induced Erk signaling by Src family kinases and the T cell protein tyrosine phosphatase.

The proinflammatory cytokine tumor necrosis factor (TNF) modulates cellular responses through the mitogen-activated protein kinase (MAPK) and nuclear factor-kappaB (NF-kappaB) signaling pathways, but the molecular mechanisms underlying MAPK activation are unknown. T cell protein tyrosine phosphatase (TCPTP) is essential for hematopoietic development and negatively regulates inflammatory responses. Using TCPTP-deficient fibroblasts, ...
we show here that TCPTP regulates TNF-induced MAPK but not NF-kappaB signaling. TCPTP interacted with the adaptor protein TRAF2, and dephosphorylated and inactivated Src tyrosine kinases to suppress downstream signaling through extracellular signal-regulated kinases and production of interleukin 6. These results link TCPTP and Src tyrosine kinases to the selective regulation of TNF-induced MAPK signaling and identify a previously unknown mechanism for modulating inflammatory responses mediated by TNF.
Mesh Terms:
Animals, Extracellular Signal-Regulated MAP Kinases, Humans, Interleukin-6, MAP Kinase Kinase Kinases, MAP Kinase Signaling System, Mitogen-Activated Protein Kinase 3, Protein Tyrosine Phosphatase, Non-Receptor Type 2, Protein Tyrosine Phosphatases, T-Lymphocytes, TNF Receptor-Associated Factor 2, Tumor Necrosis Factor-alpha, Up-Regulation, src-Family Kinases
Nat. Immunol.
Date: Mar. 01, 2005
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