MAPK14

Mitogen-activated protein kinase 14, also called p38-α, is an is_associated_with::enzyme that in humans is encoded by the MAPK14 is_associated_with::gene.

MAPK14 encodes p38α mitogen-activated protein kinase (MAPK) which is the prototypic member of the p38 MAPK family. p38 MAPKs are also known as stress-activated serine/threonine-specific kinases (SAPKs). In addition to MAPK14 for p38α, the p38 MAPK family has three additional members, including is_associated_with::MAPK11, is_associated_with::MAPK12 and is_associated_with::MAPK13 which encodes p38β, p38γ and p38δ isoforms, respectively. p38α was originally identified as a tyrosine is_associated_with::phosphorylated protein detected in activated immune cell is_associated_with::macrophages with an essential role in inflammatory cytokine induction, such as Tumor Necrotic Factor α (TNFα). However, p38α mediated kinase activity has been implicated in many tissues beyond immune systems. p38α is mainly activated through MAPK kinase kinase cascades and exerts its biological function via downstream substrate phosphorylation. p38α is implicated in diverse cellular function, from gene expression to programmed cell death through a network of signaling molecules and transcription factors. Pharmacological and genetic inhibition of p38α not only revealed its biological significance in physiological function but also the potential of targeting p38α in human diseases such as immune disorder and heart failure.

Structure
MAPK14 is a 41 kDa protein composed of 360 amino acids.

Function
The protein encoded by this gene is a member of the is_associated_with::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 is_associated_with::kinase is activated by various environmental stresses and proinflammatory is_associated_with::cytokines. The activation requires its is_associated_with::phosphorylation by is_associated_with::MAP kinase kinases (MKKs), or its is_associated_with::autophosphorylation triggered by the interaction of MAP3K7IP1/TAB1 protein with this kinase. The substrates of this kinase include transcription regulator is_associated_with::ATF2, is_associated_with::MEF2C, and MAX, cell cycle regulator CDC25B, and tumor suppressor is_associated_with::p53, which suggest the roles of this kinase in stress-related transcription and is_associated_with::cell cycle regulation, as well as in genotoxic stress response. Four alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported.

p38α is ubiquitously expressed in many cell types, in contrast, p38β is highly expressed in brain and lung, p38γ mostly in skeletal muscle and nerve system, and p38δ in uterus and pancreas. Like all MAP kinases, p38α has 11 conserved domains (Domains I to XI) and a Thr-Gly-Tyr (TGY) dual phosphorylation motif. Activation of p38 pathway has been implicated in a variety of stress response in addition to inflammation, including osmotic shock, heat, and oxidative stress. The canonical pathway for p38 activation involve a cascade of protein kinases, including MAP3K such as MEKK1, 2, 3 and 4, TGFβ-activated kinase (TAK1), TAO1-3, mixed-lineage kinase 2/3 (MLK2/3), and apoptosis signal-regulating kinase 1/2 (ASK1/2), as well as MAP2Ks, such as MKK3, 6 and 4. MAP2K mediated phosphorylation of the TGY motif results in conformational change of p38 which allows kinase activation and accessibility to substrates. In addition, TAK1-binding protein 1 (TAB1) and ZAP70 can induce p38 via non-canonical autophosphorylation. Furthermore, acetylation of p38 at lys-53 of the ATP-binding pocket also enhances p38 activity during cellular stress Under basal conditions, p38α is detected in both the nucleus and the cytoplasm. One of the consequences of p38 activation is trans-locates into the nucleus. involving both p38 phosphorylation and microtuble- and dynein-dependent process. In addition, one substrate of p38, MAP kinase-activated protein kinase 2 (MAPAK2 or MK2) can modulate and direct p38α localization to cytosole via direct interaction. p38α activation can be reserved by dephosphorylation of the TGY motif carried out by protein phosphatases, including ser-thr protein phosphatases (PPs), protein tyrosine phosphatases (PTP), and dual-specificity phosphatases (DUSP). For example, ser/thr phosphatases PP2Cα/β suppress activity of p38s through direct interaction as well as suppression of MKKs/TAK1 in mammalian cells. Hematopoietic PTP (HePTP) and striatal-enriched phosphatase (STEP) bind to MAPKs through a kinase-interaction motif (KIM) and inactivates them by dephosphorylating the phosphotyrosine residue in their activation loop. DUSPs, which has a docking domain to MAPKs and dual-specific phosphatase activity, can also bind to p38s and dephosphorylate of both phosphotyrosine and phosphothreonine residues. In addition to these phosphatases, other molecular components such as Hsp90-Cdc37 chaperone complex can also modulate p38 autophosphorylation activity and prevents non-canonical activation.

p38α MAPK is implicated in cell survival/apoptosis, proliferation, differentiation, migration, mRNA stability, and inflammatory response in different cell types through variety of different target molecules MK2 is one of the well-studied downstream targets of p38α. Their downstream substrates include small heat shock protein 27 (HSP27), lymphocyte-specific protein1 (LSP1), cAMP response element-binding protein (CREB), cyclooxygenase 2 (COX2), activating transcription factor 1 (ATF1), serum response factor (SRF), and mRNA-binding protein tristetraprolin (TTP)  In addition to protein kinases, many transcription factors are downstream targets of p38α, including ATF1/2/6, c-Myc, c-FOS, GATA4, MEF2A/C, SRF, STAT1, and CHOP

Role in cardiovascular system
p38α constitutes the main p38 MAPK activity in heart. During cardiomyocyte maturation in new born mouse heart, p38α activity can regulate myocyte cytokinesis and promote cell cycle exit. while inhibition of p38 activity leads to induction of mitosis in both adult and fetal cardiomyocyte. Therefore, p38 is associated with cell-cycle arrest in mammalian cardiomyocytes and its inhibition may represent a strategy to promote cardiac regeneration in response to injury. In addition, p38α induction promotes myocyte apoptosis. via downstream targets STAT1, CHOP, FAK, SMAD, cytochrome c, NF-kB, PTEN, and p53. p38 can also target IRS-1 mediated AKT signaling and promotes myocyte death under chronic insulin stimulation. Inhibition of p38 activity confers cardioprotection against ischemia reperfusion injury in heart However, some reports demonstrated that p38 also involves in anti-apoptotic effect via phosphorylation of αβ-Crystallin or induction of Pim-3 during early response to oxidative stress or anoxic preconditioning respectively    More interestingly, p38α and p38β appear to have an opposite role in apoptosis. Whereas p38α has a pro-apoptotic role via p53 activation, p38β has a pro-survival role via inhibition of ROS formation. In general, chronic activation of p38 activity is viewed as pathological and pro-apoptotic, and inhibition of p38 activity is in clinical evaluation as a potential therapy to mitigate acute injury in ischemic heart failure. p38 activity is also implicated in cardiac hypertrophy which is a significant feature of pathological remodeling in the diseased hearts and a major risk factor for heart failure and advert outcome. Most in vitro evidence supports that p38 activation promotes cardiomyocyte hypertrophy. However, in vivo evidence suggest that chronic activation of p38 activity triggers restrictive cardiomyopathy with limited hypertrophy, while genetic inactivation p38α in mouse heart results in an elevated cardiac hypertrophy in response to pressure overload or swimming exercise. Therefore, the functional role of p38 in cardiac hypertrophy remains controversial and yet to be further elucidated.

Interactions
MAPK14 has been shown to interact with:


 * is_associated_with::AKT1,
 * ATF2,
 * is_associated_with::CDC25B,
 * is_associated_with::CDC25C,
 * CSNK2A1,
 * is_associated_with::DUSP10,
 * is_associated_with::DUSP16,
 * is_associated_with::DUSP1,
 * FUBP1,
 * HTRA2,
 * KRT8
 * is_associated_with::MAP2K6,
 * is_associated_with::MAP3K7IP1,
 * is_associated_with::MAPK1,
 * MEF2A,
 * is_associated_with::MAPKAPK3,
 * MEF2A,
 * is_associated_with::RPS6KA4, and
 * is_associated_with::ZFP36L1.