MAPKAPK2
Description
The MAPKAPK2 (MAPK activated protein kinase 2) is a protein-coding gene located on chromosome 1.
MAP kinase-activated protein kinase 2 is an enzyme that in humans is encoded by the MAPKAPK2 gene.
== Function == This gene encodes a member of the Ser/Thr protein kinase family. This kinase is regulated through direct phosphorylation by p38 MAP kinase. In conjunction with p38 MAP kinase, this kinase is known to be involved in many cellular processes including stress and inflammatory responses, nuclear export, gene expression regulation and cell proliferation. Heat shock protein HSP27 was shown to be its major direct substrate in vivo. Two transcript variants encoding two different isoforms have been found for this gene.
=== Vascular barrier === MK2 pathway has been demonstrated to have a key role in maintaining and repairing the integrity of endothelial barrier in the lung via actin and vimentin remodeling. Activation of MK2 via its phosphorylation by p38 has been shown to restore the vascular barrier and repair vascular leak, associated with over 60 medical conditions, including Acute Respiratory Distress Syndrome (ARDS), a major cause of death around the world.
=== SASP initiation === MAPKAPK2 mediates the initiation of the senescence-associated secretory phenotype (SASP) by mTOR (mechanistic target of rapamycin). Interleukin 1 alpha (IL1A) is found on the surface of senescent cells, where it contributes to the production of SASP factors due to a positive feedback loop with NF-κB. Translation of mRNA for IL1A is highly dependent upon mTOR activity.
MAPKAPK2, also known as MK2, is a stress-activated serine/threonine protein kinase that plays a crucial role in various cellular processes, including cytokine production, endocytosis, cytoskeleton reorganization, cell migration, cell cycle control, chromatin remodeling, DNA damage response, and transcriptional regulation. It is activated upon stress by phosphorylation through MAP kinase p38-alpha/MAPK14, subsequently phosphorylating specific substrates. MAPKAPK2 preferentially phosphorylates serine residues within the peptide sequence Hyd-X-R-X(2)-S, where Hyd represents a large hydrophobic residue. Its known substrates include ALOX5, CDC25B, CDC25C, CEP131, ELAVL1, HNRNPA0, HSP27/HSPB1, KRT18, KRT20, LIMK1, LSP1, PABPC1, PARN, PDE4A, RCSD1, RPS6KA3, TAB3, and TTP/ZFP36. MAPKAPK2's phosphorylation of HSF1 promotes its interaction with HSP90 proteins, inhibiting its homotrimerization, DNA-binding, and transactivation activities. In response to stress, MAPKAPK2 mediates the phosphorylation of HSP27/HSPB1, leading to its dissociation from large small heat-shock protein (sHsps) oligomers. This disruption impairs their chaperone activities and their ability to effectively protect against oxidative stress. MAPKAPK2 significantly contributes to the inflammatory response by regulating the post-transcriptional production of tumor necrosis factor (TNF) and IL6. It achieves this by phosphorylating AU-rich elements (AREs)-binding proteins such as ELAVL1, HNRNPA0, PABPC1, and TTP/ZFP36, thereby influencing the stability and translation of TNF and IL6 mRNAs. The phosphorylation of TTP/ZFP36, a key post-transcriptional regulator of TNF, enhances its binding to 14-3-3 proteins and reduces its affinity for ARE mRNA, resulting in the inhibition of dependent degradation of ARE-containing transcripts. MAPKAPK2 also plays a role in cellular stress responses induced by ultraviolet irradiation by phosphorylating CEP131. This phosphorylation promotes CEP131's binding to 14-3-3 proteins, ultimately inhibiting the formation of novel centriolar satellites. Furthermore, MAPKAPK2 is involved in the late G2/M checkpoint following DNA damage through a mechanism of post-transcriptional mRNA stabilization. Upon DNA damage, it relocates from the nucleus to the cytoplasm and phosphorylates HNRNPA0 and PARN, leading to the stabilization of GADD45A mRNA. In dendritic cells, MAPKAPK2 participates in the toll-like receptor signaling pathway (TLR) by phosphorylating and activating RPS6KA3, a step required for acute TLR-induced macropinocytosis. MAPKAPK2 forms a stable complex with p38-alpha/MAPK14, creating a heterodimer where the ATP-binding sites of both kinases are positioned 'face to face' at the heterodimer interface. Additionally, MAPKAPK2 interacts with PHC2 and HSF1.
MAPKAPK2 is also known as MAPKAP-K2, MK-2, MK2.
