MAP3K2
MAP3K2, also known as MEKK2, is a serine/threonine MAP kinase kinase kinase that activates downstream MAPK signaling, including JNK, ERK5, and NF-κB-linked kinase modules[1][2][3]. Mechanistically, MEKK2 forms dimers that support autophosphorylation and substrate recognition, providing a structural basis for MAP3K2 pathway activation[4][5]. In immune and inflammatory models, MEKK2 disruption reduces cytokine production after IgE and c-Kit stimulation in mast-cell systems, linking MAP3K2 to experimentally tractable signaling outputs[6]. In intestinal injury models, MAP3K2-regulated stromal cells use a ROS-MAP3K2-ERK5-KLF2 axis to enhance R-spondin 1 and support WNT-dependent epithelial regeneration[7]. Compared with the related isoform MEKK3, MEKK2 shows different pathway selectivity: early cloning and kinase studies reported stronger MEKK2 coupling to JNK, whereas MEKK3 preferentially activated p42/44 MAPK or MKK3-related signaling in specific assays[1][8]. In cancer models, SMYD3 methylates MAP3K2 at lysine 260, increases Ras/Raf/MEK/ERK signaling, and supports Ras-driven carcinoma formation[9]. For experimental applications, ponatinib and several known kinase inhibitors show potent MEKK2 inhibitory activity, while structural MEKK2-ponatinib data provide a framework for inhibitor design[10][4].
References:
- [1]. Blank JL, et al. Molecular cloning of mitogen-activated protein/ERK kinase kinases (MEKK) 2 and 3. Regulation of sequential phosphorylation pathways involving mitogen-activated protein kinase and c-Jun kinase. J Biol Chem. 1996 Mar 8;271(10):5361-8. [Content Brief]
- [2]. Sun W, et al. MEKK2 associates with the adapter protein Lad/RIBP and regulates the MEK5-BMK1/ERK5 pathway. J Biol Chem. 2001 Feb 16;276(7):5093-100. [Content Brief]
- [3]. Zhao Q, et al. Mitogen-activated protein kinase/ERK kinase kinases 2 and 3 activate nuclear factor-kappaB through IkappaB kinase-alpha and IkappaB kinase-beta. J Biol Chem. 1999 Mar 26;274(13):8355-8. [Content Brief]
- [4]. Vish KJ, et al. Structural basis for MEKK2 dimerization and substrate recognition. Nat Commun. 2025 Nov 29;17(1):193. [Content Brief]
- [5]. Cheng J, et al. Dimerization through the catalytic domain is essential for MEKK2 activation. J Biol Chem. 2005 Apr 8;280(14):13477-82. [Content Brief]
- [6]. Garrington TP, et al. MEKK2 gene disruption causes loss of cytokine production in response to IgE and c-Kit ligand stimulation of ES cell-derived mast cells. EMBO J. 2000 Oct 16;19(20):5387-95. [Content Brief]
- [7]. Wu N, et al. MAP3K2-regulated intestinal stromal cells define a distinct stem cell niche. Nature. 2021 Apr;592(7855):606-610. [Content Brief]
- [8]. Deacon K, et al. Characterization of the mitogen-activated protein kinase kinase 4 (MKK4)/c-Jun NH2-terminal kinase 1 and MKK3/p38 pathways regulated by MEK kinases 2 and 3. MEK kinase 3 activates MKK3 but does not cause activation of p38 kinase in vivo. J Biol Chem. 1997 May 30;272(22):14489-96. [Content Brief]
- [9]. Mazur PK, et al. SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer. Nature. 2014 Jun 12;510(7504):283-7. [Content Brief]
- [10]. Ahmad S, et al. Identification of ponatinib and other known kinase inhibitors with potent MEKK2 inhibitory activity. Biochem Biophys Res Commun. 2015 Aug 7;463(4):888-93. [Content Brief]
