Abstract

A key step by which tumor necrosis factor (TNF) signals the activation of nuclear factor-kappaB (NF-kappaB) and the stress-activated protein kinase (SAPK, also called c-Jun N-terminal kinase or JNK) is the recruitment to the TNF receptor of TNF receptor-associated factor 2 (TRAF2). However, the subsequent steps in TRAF2-induced SAPK and NF-kappaB activation remain unresolved. Here we report the identification of a TNF-responsive serine/threonine protein kinase termed GCK related (GCKR) that likely signals via mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase kinase 1 (MEKK1) to activate the SAPK pathway. TNF, TRAF2, and ultraviolet (UV) light, which in part uses the TNF receptor signaling pathway, all increased GCKR activity. A TRAF2 mutant, which inhibits both TRAF2-induced NF-kappaB and SAPK activation, blocked TNF-induced GCKR activation. Finally, interference with GCKR expression impeded TRAF2- and TNF-induced SAPK activation but not that of NF-kappaB. This suggests a divergence in the TNF signaling pathway that leads to SAPK and NF-kappaB activation, which is located downstream of TRAF2 but upstream of GCKR.

Highlights

  • From the B Cell Molecular Immunology Section, Laboratory of Immunoregulation, NIAID, National Institutes of Health, Bethesda, Maryland 20892-1876

  • We report the identification of a tumor necrosis factor (TNF)-responsive serine/threonine protein kinase termed GCK related (GCKR) that likely signals via mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase kinase 1 (MEKK1) to activate the SAPK pathway

  • Since UV light utilizes other cell surface receptors besides the TNF receptor in activating SAPK in HeLa cells [27], we examined the effects of optimal concentrations of interleukin-1 (IL-1), epidermal growth factor (EGF), and TNF on GCKR in those cells

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Summary

THE JOURNAL OF BIOLOGICAL CHEMISTRY

Vol 272, No 51, Issue of December 19, pp. 32102–32107, 1997 Printed in U.S.A. Activation of Stress-activated Protein Kinase/c-Jun N-terminal Kinase, but Not NF-␬B, by the Tumor Necrosis Factor (TNF) Receptor 1 through a TNF Receptor-associated Factor 2- and Germinal Center Kinase Related-dependent Pathway*. We report the identification of a TNF-responsive serine/threonine protein kinase termed GCK related (GCKR) that likely signals via mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase kinase 1 (MEKK1) to activate the SAPK pathway. Interference with GCKR expression impeded TRAF2- and TNF-induced SAPK activation but not that of NF-␬B. Two other MEKKs, both of which are implicated in TNF-signaling, are NIK, which interacts with TRAF2 and signals NF-␬B activation [18], and ASK1, which is TNF-inducible and activates the SAPK pathway and the related p38 pathway [19]. Here we report the identification of a third family member termed GCK related (GCKR) that is widely distributed, TNF-responsive, and a major mediator of TNF-induced SAPK activation

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