Mitogen-activated protein kinase kinase kinase kinase 2

Definition:

Serine/threonine-protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Acts as a MAPK kinase kinase kinase (MAP4K) and is an upstream activator of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway and to a lesser extent of the p38 MAPKs signaling pathway. Required for the efficient activation of JNKs by TRAF6-dependent stimuli, including pathogen-associated molecular patterns (PAMPs) such as polyinosine-polycytidine (poly(IC)), lipopolysaccharides (LPS), lipid A, peptidoglycan (PGN), or bacterial flagellin. To a lesser degree, IL-1 and engagement of CD40 also stimulate MAP4K2-mediated JNKs activation. The requirement for MAP4K2/GCK is most pronounced for LPS signaling, and extends to LPS stimulation of c-Jun phosphorylation and induction of IL-8. Enhances MAP3K1 oligomerization, which may relieve N-terminal mediated MAP3K1 autoinhibition and lead to activation following autophosphorylation. Mediates also the SAP/JNK signaling pathway and the p38 MAPKs signaling pathway through activation of the MAP3Ks MAP3K10/MLK2 and MAP3K11/MLK3. May play a role in the regulation of vesicle targeting or fusion. regulation of vesicle targeting or fusion.

References:

[1]. Jian Zhong, et al. 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. Mol Cell Biol. 2004 Oct;24(20):9165-75. [Content Brief]

[2]. C M Pombo, et al. Activation of the SAPK pathway by the human STE20 homologue germinal centre kinase. Nature. 1995 Oct 26;377(6551):750-4. [Content Brief]

[3]. T Yuasa, et al. Tumor necrosis factor signaling to stress-activated protein kinase (SAPK)/Jun NH2-terminal kinase (JNK) and p38. Germinal center kinase couples TRAF2 to mitogen-activated protein kinase/ERK kinase kinase 1 and SAPK while receptor interacting protein associates with a mitogen-activated protein kinase kinase kinase upstream of MKK6 and p38. J Biol Chem. 1998 Aug 28;273(35):22681-92. [Content Brief]

[4]. P Katz, et al. Differential expression of a novel protein kinase in human B lymphocytes. Preferential localization in the germinal center. J Biol Chem. 1994 Jun 17;269(24):16802-9. [Content Brief]

[5]. Deborah N Chadee, et al. Direct activation of mitogen-activated protein kinase kinase kinase MEKK1 by the Ste20p homologue GCK and the adapter protein TRAF2. Mol Cell Biol. 2002 Feb;22(3):737-49. [Content Brief]

[6]. Jian Zhong, et al. Dissection of a signaling pathway by which pathogen-associated molecular patterns recruit the JNK and p38 MAPKs and trigger cytokine release. J Biol Chem. 2007 Aug 17;282(33):24246-54. [Content Brief]

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