Mitogen-activated protein kinase-activated protein kinase 2 in complex with Mitogen-activated protein kinase 14 (p38α) (MK2-p38α complex)

The MAPKAPK2 (MK2) in complex with p38α (MAPK14) is a pivotal signaling assembly within the p38 mitogen-activated protein kinase pathway [1, 2]. This complex is formed when p38α binds to and phosphorylates MK2, a process essential for the activation and nuclear export of MK2 [3]. Once activated and exported to the cytoplasm, MK2 regulates the expression of pro-inflammatory cytokines like TNF-α and IL-6 by stabilizing their mRNA through interactions with AU-rich elements [4]. Because of its central role in inflammation, the MK2-p38α complex is a major target for treating autoimmune and inflammatory disorders [4]. While direct p38α inhibitors have struggled in clinical trials due to toxicity, targeting the MK2-p38α interaction or MK2 specifically offers a potentially safer alternative [5]. In addition to inflammation, the complex is involved in the DNA damage response, providing a rationale for its investigation in cancer therapy [4]. Current drug development efforts focus on small molecules that either inhibit the kinase domains or disrupt the protein-protein interface [5]. Monitoring the phosphorylation state of MK2 serves as a key biomarker for the activity of this signaling node [5]. Sources: [1] UniProt P49137; [2] UniProt Q16539; [3] Ter Haar et al. (2007) J. Biol. Chem.; [4] Gaestel (2006) Nat Rev Mol Cell Biol.; [5] ClinicalTrials.gov (NCT03516747).

Other names

MAPKAPK2-MAPK14 complexMK2-p38 alpha complexp38-MK2 signaling modulep38-MAPKAPK2 complex

Inhibition of p38α or MK2 kinase activity, or disruption of the protein-protein interaction between p38α and MK2 to prevent downstream signaling and cytokine production.