MAP2K3

MAP2K3 Full Name

mitogen-activated protein kinase kinase 3

MAP2K3 Introduction

MAP2K3 (also known as MKK3 or MEK3) is a dual-specificity kinase that phosphorylates and activates the p38 MAPK family in response to inflammatory cytokines and cellular stress. The protein preferentially activates p38α (MAPK14) and p38β (MAPK11) rather than p38γ or p38δ, and it participates in stress-activated signaling cascades downstream of cytokine receptors, Toll-like receptors, and environmental insults such as UV and oxidative stress. The MAP2K3 gene is located on chromosome 17q24.2 and is broadly expressed.

Figure 1. TMAP2K3: the central kinase of the p38 mapk pathway

Stress-Activated p38 MAPK Cascade
On activation by upstream MKKKs such as TAK1, ASK1, or MLK3, MAP2K3 phosphorylates p38α/β on the conserved TGY motif in their activation loops, enabling p38 to phosphorylate a wide range of substrates including the transcription factors ATF2, MEF2C, and C/EBP, as well as the kinase MK2. The resulting signaling regulates cytokine production, cell-cycle checkpoints, and apoptosis in response to inflammatory stress. Genetic ablation of MAP2K3 in mice impairs p38 activation in macrophages and cardiomyocytes and reduces the production of TNFα and IL-6 in response to lipopolysaccharide.

Inflammation, Cardiac Disease, and Cancer
MAP2K3-deficient mice are protected from inflammatory bone loss and from cardiac remodeling after pressure overload, identifying MAP2K3 as a candidate target in chronic inflammatory and cardiovascular disease. In cancer, MAP2K3 has context-dependent roles: it can act as a tumor suppressor by promoting stress-induced apoptosis, or as a tumor promoter by sustaining inflammatory cytokine signaling. Selective MAP2K3 inhibitors are being explored for inflammatory conditions, although the redundancy with MAP2K6 in activating p38 has made it difficult to achieve clean pharmacological separation.

Alternate Names for MAP2K3

MAP2K3; mitogen-activated protein kinase kinase 3; MEK3; MKK3; MAPKK3; PRKMK3; SAPKK2; SAPKK-2; dual specificity mitogen-activated protein kinase kinase 3; MEK 3; MAPKK 3; SAPK kinase 2; MAPK/ERK kinase 3; MAP kinase kinase 3; stress-activated protein kinase kinase 2;