MAP4K2

The protein encoded by this gene is a member of the serine/threonine protein kinase family. Although this kinase is found in many tissues, its expression in lymphoid follicles is restricted to the cells of germinal centre, where it may participate in B-cell differentiation. This kinase can be activated by TNF-alpha, and has been shown to specifically activate MAP kinases. This kinase is also found to interact with TNF receptor-associated factor 2 (TRAF2), which is involved in the activation of MAP3K1/MEKK1. Alternative splicing results in multiple transcript variants.

Full Name

MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE KINASE 2

Function

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.

Biological Process

Immune responseManual Assertion Based On ExperimentTAS:ProtInc
Innate immune responseIEA:UniProtKB-KW
Intracellular signal transductionManual Assertion Based On ExperimentIDA:UniProtKB
JNK cascadeManual Assertion Based On ExperimentTAS:ProtInc
Positive regulation of JNK cascadeManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of JUN kinase activityManual Assertion Based On ExperimentIDA:UniProtKB
Protein phosphorylationManual Assertion Based On ExperimentIDA:UniProtKB
Vesicle targetingIEA:Ensembl

Cellular Location

Cytoplasm
Basolateral cell membrane
Golgi apparatus membrane

PTM

Polyubiquitinated through 'Lys-48'-polyubiquitin chains, allowing proteasomal turnover. Ubiquitination requires the kinase activity of MAP4K2/GCK.
Autophosphorylated in response to tumor necrosis factor (TNF), endotoxins or pro-inflammatory stimuli. Autophosphorylation leads to activation.