MAPK11

Description

The MAPK11 (mitogen-activated protein kinase 11) is a protein-coding gene located on chromosome 22.

Mitogen-activated protein kinase 11 is an enzyme that in humans is encoded by the MAPK11 gene. The protein encoded by this gene is a member of the MAP kinase family. MAP kinases act as an integration point for multiple biochemical signals, and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation, and development. This kinase is most closely related to p38 MAP kinase, both of which can be activated by proinflammatory cytokines and environmental stress. This kinase is activated through its phosphorylation by MAP kinase kinases (MKKs), preferably by MKK6. Transcription factor ATF2/CREB2 has been shown to be a substrate of this kinase. MAPK11 has been shown to interact with HDAC3 and Promyelocytic leukemia protein.

MAPK11 is a serine/threonine kinase that plays a critical role in the MAP kinase signal transduction pathway. It is one of four p38 MAPKs, which are activated by extracellular stimuli like pro-inflammatory cytokines and physical stress. These kinases then activate transcription factors, leading to cellular responses. p38 MAPKs are known to phosphorylate a wide range of proteins, with an estimated 200-300 substrates each. MAPK11's functions overlap significantly with those of MAPK14. MAPK11's downstream targets include kinases that further phosphorylate additional targets. For example, RPS6KA5/MSK1 and RPS6KA4/MSK2 directly activate transcription factors like CREB1, ATF1, RELA/NFKB3, STAT1, and STAT3, as well as phosphorylating histone H3 and HMGN1. These kinases are crucial for the rapid induction of immediate-early genes in response to stress or mitogenic stimuli, achieving this through chromatin remodeling and transcription machinery recruitment. Other targets of MAPK11, such as MAPKAPK2/MK2 and MAPKAPK3/MK3, regulate gene expression primarily at the post-transcriptional level by phosphorylating ZFP36 and ELAVL1 and regulating EEF2K, which is essential for mRNA elongation during translation. MKNK1/MNK1 and MKNK2/MNK2, additional kinases activated by p38 MAPKs, regulate protein synthesis through phosphorylation of EIF4E2. In the cytoplasm, the p38 MAPK pathway plays a key role in regulating protein turnover. For example, CFLAR, an inhibitor of TNF-induced apoptosis, undergoes proteasome-mediated degradation regulated by p38 MAPK phosphorylation. Additionally, p38 MAPKs regulate the ectodomain shedding of transmembrane proteins. Upon inflammatory stimuli, p38 MAPKs phosphorylate ADAM17, a membrane-associated metalloprotease. This phosphorylation is crucial for ADAM17-mediated ectodomain shedding of TGF-alpha family ligands, ultimately activating EGFR signaling and cell proliferation. FGFR1, another p38 MAPK substrate, can be translocated from the extracellular space into the cytosol and nucleus of target cells, regulating processes like rRNA synthesis and cell growth. FGFR1 translocation requires p38 MAPK activation. In the nucleus, various transcription factors are phosphorylated and activated by p38 MAPKs in response to diverse stimuli. These include ATF1, ATF2, ATF6, ELK1, PTPRH, DDIT3, TP53/p53, and MEF2C and MEF2A. p38 MAPKs are becoming recognized as important modulators of gene expression through their regulation of chromatin modifiers and remodelers. The promoters of genes associated with the inflammatory response, such as IL6, IL8, and IL12B, exhibit p38 MAPK-dependent enrichment of histone H3 phosphorylation on 'Ser-10' (H3S10ph) in LPS-stimulated myeloid cells. This phosphorylation enhances the accessibility of cryptic NF-kappa-B-binding sites, facilitating increased NF-kappa-B recruitment. MAPK11 phosphorylates NLRP1 downstream of MAP3K20/ZAK in response to UV-B irradiation and ribosome collisions, promoting the activation of the NLRP1 inflammasome and pyroptosis. It interacts with HDAC3 and DUSP16.

MAPK11 is also known as P38B, P38BETA2, PRKM11, SAPK2, SAPK2B, p38-2, p38Beta.

Associated Diseases

WES Whole Exome Sequencing