MAP3K2

MAP3K2 Full Name

mitogen-activated protein kinase kinase kinase 2

MAP3K2 Introduction

MAP3K2 (MEKK2) is a serine/threonine kinase that activates the JNK and ERK5 pathways in response to cytokines, growth factors, and stress. It forms a functional pair with MAP3K1 (MEKK1) but has distinct expression patterns and contributes to different physiological processes, particularly in the immune and skeletal systems. The MAP3K2 gene maps to chromosome 2q14.3, and the encoded protein is widely expressed but enriched in hematopoietic and mesenchymal lineages.

Figure 1. The structure of MAP3K2.

MAP2K Activation in Immune and Stress Signaling
MAP3K2 phosphorylates MAP2K7 and MAP2K4 to activate the JNK pathway, and MAP2K5 to activate ERK5, transmitting signals from receptors such as the TNF receptor, IL-1 receptor, and selected receptor tyrosine kinases. In T cells, MAP3K2 regulates JNK-driven AP-1 activation and the production of IL-2, while in macrophages it contributes to cytokine production downstream of Toll-like receptors. MAP3K2 also activates IKK and NF-κB in response to specific stresses, integrating inflammation and stress responses at the level of MAP3K scaffolding.

Cancer, Inflammation, and Skeletal Disease
MAP3K2 amplification has been reported in several cancers, including prostate and lung adenocarcinoma, where it drives JNK-mediated AP-1 activation and tumor proliferation. In prostate cancer, MAP3K2 supports ligand-independent AR signaling and contributes to castration resistance. Pharmacological MAP3K2 inhibitors have shown efficacy in preclinical models of inflammatory arthritis and of cytokine-driven cachexia. Recent work also links MAP3K2 to osteoclast differentiation, suggesting that MAP3K2 blockade could be combined with anti-resorptive agents in diseases such as osteoporosis and rheumatoid arthritis.

Alternate Names for MAP3K2

MAP3K2; mitogen-activated protein kinase kinase kinase 2; MEKK2; MEKK2B; MEKK 2; MEK kinase 2; MAP/ERK kinase kinase 2; MAPK/ERK kinase kinase 2;