Germinal Center Kinase Is Required for Optimal Jun N-Terminal Kinase Activation by Toll-Like Receptor Agonists and Is Regulated by the Ubiquitin Proteasome System and Agonist-Induced, TRAF6-Dependent Stabilization
Year: 2004
Type: article
Abstract: Germinal center kinase (GCK), a member of the Ste20 family, selectively activates the Jun N-terminal kinase (JNK) group of mitogen-activated protein kinases. Here, we show that endogenous GCK is activated by polyinosine-polycytidine [poly(IC)] and lipopolysaccharides (LPS), lipid A, interleukin-1 (IL-1), and engagement of CD40, all agonists that require TRAF6 for JNK activation. RNA interference experiments indicate that GCK is required for the maximal activation of JNK by LPS, lipid A, poly(IC), and, to a lesser extent, IL-1 and engagement of CD40. GCK is ubiquitinated in situ and stabilized by inhibitors of the proteasome, indicating that GCK is subject to proteasomal turnover. GCK is constitutively active, and the kinase activity of GCK is required for GCK ubiquitination. Agonist activation of GCK involves the TRAF6-dependent transient stabilization of the GCK polypeptide rather than an increase in intrinsic kinase activity. Our results identify a physiologic function and unexpected mode of regulation for GCK.
Source: Molecular and Cellular Biology
Authors: Jian Zhong, John M. Kyriakis
Institutions: Tufts University, Tufts Medical Center
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2108163344