MK14_PANTR
ID MK14_PANTR Reviewed; 360 AA.
AC Q95NE7;
DT 13-DEC-2002, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 3.
DT 03-AUG-2022, entry version 151.
DE RecName: Full=Mitogen-activated protein kinase 14 {ECO:0000250|UniProtKB:P47811};
DE Short=MAP kinase 14;
DE Short=MAPK 14;
DE EC=2.7.11.24 {ECO:0000250|UniProtKB:Q16539};
DE AltName: Full=Mitogen-activated protein kinase p38 alpha;
DE Short=MAP kinase p38 alpha;
DE AltName: Full=Stress-activated protein kinase 2a;
GN Name=MAPK14 {ECO:0000250|UniProtKB:P47811}; Synonyms=CSBP1;
OS Pan troglodytes (Chimpanzee).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Pan.
OX NCBI_TaxID=9598 {ECO:0000312|EMBL:AAF36771.1};
RN [1] {ECO:0000312|EMBL:AAF36771.1}
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=10727080; DOI=10.3109/10425179909033952;
RA Herbison C.E., Sayer D.C., Bellgard M., Allcock R.J.N., Christiansen F.T.,
RA Price P.;
RT "Structure and polymorphism of two stress-activated protein kinase genes
RT centromeric of the MHC: SAPK2a and SAPK4.";
RL DNA Seq. 10:229-243(1999).
CC -!- FUNCTION: Serine/threonine kinase which acts as an essential component
CC of the MAP kinase signal transduction pathway. MAPK14 is one of the
CC four p38 MAPKs which play an important role in the cascades of cellular
CC responses evoked by extracellular stimuli such as pro-inflammatory
CC cytokines or physical stress leading to direct activation of
CC transcription factors. Accordingly, p38 MAPKs phosphorylate a broad
CC range of proteins and it has been estimated that they may have
CC approximately 200 to 300 substrates each. Some of the targets are
CC downstream kinases which are activated through phosphorylation and
CC further phosphorylate additional targets. RPS6KA5/MSK1 and RPS6KA4/MSK2
CC can directly phosphorylate and activate transcription factors such as
CC CREB1, ATF1, the NF-kappa-B isoform RELA/NFKB3, STAT1 and STAT3, but
CC can also phosphorylate histone H3 and the nucleosomal protein HMGN1.
CC RPS6KA5/MSK1 and RPS6KA4/MSK2 play important roles in the rapid
CC induction of immediate-early genes in response to stress or mitogenic
CC stimuli, either by inducing chromatin remodeling or by recruiting the
CC transcription machinery. On the other hand, two other kinase targets,
CC MAPKAPK2/MK2 and MAPKAPK3/MK3, participate in the control of gene
CC expression mostly at the post-transcriptional level, by phosphorylating
CC ZFP36 (tristetraprolin) and ELAVL1, and by regulating EEF2K, which is
CC important for the elongation of mRNA during translation. MKNK1/MNK1 and
CC MKNK2/MNK2, two other kinases activated by p38 MAPKs, regulate protein
CC synthesis by phosphorylating the initiation factor EIF4E2. MAPK14
CC interacts also with casein kinase II, leading to its activation through
CC autophosphorylation and further phosphorylation of TP53/p53. In the
CC cytoplasm, the p38 MAPK pathway is an important regulator of protein
CC turnover. For example, CFLAR is an inhibitor of TNF-induced apoptosis
CC whose proteasome-mediated degradation is regulated by p38 MAPK
CC phosphorylation. In a similar way, MAPK14 phosphorylates the ubiquitin
CC ligase SIAH2, regulating its activity towards EGLN3. MAPK14 may also
CC inhibit the lysosomal degradation pathway of autophagy by interfering
CC with the intracellular trafficking of the transmembrane protein ATG9.
CC Another function of MAPK14 is to regulate the endocytosis of membrane
CC receptors by different mechanisms that impinge on the small GTPase
CC RAB5A. In addition, clathrin-mediated EGFR internalization induced by
CC inflammatory cytokines and UV irradiation depends on MAPK14-mediated
CC phosphorylation of EGFR itself as well as of RAB5A effectors.
CC Ectodomain shedding of transmembrane proteins is regulated by p38 MAPKs
CC as well. In response to inflammatory stimuli, p38 MAPKs phosphorylate
CC the membrane-associated metalloprotease ADAM17. Such phosphorylation is
CC required for ADAM17-mediated ectodomain shedding of TGF-alpha family
CC ligands, which results in the activation of EGFR signaling and cell
CC proliferation. Another p38 MAPK substrate is FGFR1. FGFR1 can be
CC translocated from the extracellular space into the cytosol and nucleus
CC of target cells, and regulates processes such as rRNA synthesis and
CC cell growth. FGFR1 translocation requires p38 MAPK activation. In the
CC nucleus, many transcription factors are phosphorylated and activated by
CC p38 MAPKs in response to different stimuli. Classical examples include
CC ATF1, ATF2, ATF6, ELK1, PTPRH, DDIT3, TP53/p53 and MEF2C and MEF2A. The
CC p38 MAPKs are emerging as important modulators of gene expression by
CC regulating chromatin modifiers and remodelers. The promoters of several
CC genes involved in the inflammatory response, such as IL6, IL8 and
CC IL12B, display a p38 MAPK-dependent enrichment of histone H3
CC phosphorylation on 'Ser-10' (H3S10ph) in LPS-stimulated myeloid cells.
CC This phosphorylation enhances the accessibility of the cryptic NF-
CC kappa-B-binding sites marking promoters for increased NF-kappa-B
CC recruitment. Phosphorylates CDC25B and CDC25C which is required for
CC binding to 14-3-3 proteins and leads to initiation of a G2 delay after
CC ultraviolet radiation. Phosphorylates TIAR following DNA damage,
CC releasing TIAR from GADD45A mRNA and preventing mRNA degradation. The
CC p38 MAPKs may also have kinase-independent roles, which are thought to
CC be due to the binding to targets in the absence of phosphorylation.
CC Protein O-Glc-N-acylation catalyzed by the OGT is regulated by MAPK14,
CC and, although OGT does not seem to be phosphorylated by MAPK14, their
CC interaction increases upon MAPK14 activation induced by glucose
CC deprivation. This interaction may regulate OGT activity by recruiting
CC it to specific targets such as neurofilament H, stimulating its O-Glc-
CC N-acylation. Required in mid-fetal development for the growth of
CC embryo-derived blood vessels in the labyrinth layer of the placenta.
CC Also plays an essential role in developmental and stress-induced
CC erythropoiesis, through regulation of EPO gene expression (By
CC similarity). Phosphorylates S100A9 at 'Thr-113' (By similarity).
CC {ECO:0000250|UniProtKB:Q16539}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.24;
CC Evidence={ECO:0000250|UniProtKB:Q16539};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.24; Evidence={ECO:0000250|UniProtKB:Q16539};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:Q16539};
CC -!- ACTIVITY REGULATION: Activated by cell stresses such as DNA damage,
CC heat shock, osmotic shock, anisomycin and sodium arsenite, as well as
CC pro-inflammatory stimuli such as bacterial lipopolysaccharide (LPS) and
CC interleukin-1. Activation occurs through dual phosphorylation of Thr-
CC 180 and Tyr-182 by either of two dual specificity kinases, MAP2K3/MKK3
CC or MAP2K6/MKK6, and potentially also MAP2K4/MKK4, as well as by TAB1-
CC mediated autophosphorylation. MAPK14 phosphorylated on both Thr-180 and
CC Tyr-182 is 10-20-fold more active than MAPK14 phosphorylated only on
CC Thr-180, whereas MAPK14 phosphorylated on Tyr-182 alone is inactive.
CC whereas Thr-180 is necessary for catalysis, Tyr-182 may be required for
CC auto-activation and substrate recognition. Phosphorylated at Tyr-323 by
CC ZAP70 in an alternative activation pathway in response to TCR signaling
CC in T-cells. This alternative pathway is inhibited by GADD45A. Inhibited
CC by dual specificity phosphatases, such as DUSP1, DUSP10, and DUSP16.
CC Specifically inhibited by the binding of pyridinyl-imidazole compounds,
CC which are cytokine-suppressive anti-inflammatory drugs (CSAID).
CC SB203580 is an inhibitor of MAPK14 (By similarity).
CC {ECO:0000250|UniProtKB:Q16539}.
CC -!- SUBUNIT: Component of a signaling complex containing at least AKAP13,
CC PKN1, MAPK14, ZAK and MAP2K3. Within this complex, AKAP13 interacts
CC directly with PKN1, which in turn recruits MAPK14, MAP2K3 and ZAK (By
CC similarity). Binds to a kinase interaction motif within the protein
CC tyrosine phosphatase, PTPRR (By similarity). This interaction retains
CC MAPK14 in the cytoplasm and prevents nuclear accumulation (By
CC similarity). Interacts with SPAG9 and GADD45A (By similarity).
CC Interacts with CDC25B, CDC25C, DUSP1, DUSP10, DUSP16, NP60, SUPT20H and
CC TAB1. Interacts with casein kinase II subunits CSNK2A1 and CSNK2B.
CC Interacts with PPM1D. Interacts with CDK5RAP3; recruits PPM1D to MAPK14
CC and may regulate its dephosphorylation (By similarity). Interacts with
CC DUSP2; this interaction does not lead to catalytic activation of DUSP2
CC and dephosphrylation of MAPK14 (By similarity). {ECO:0000250,
CC ECO:0000250|UniProtKB:P47811, ECO:0000250|UniProtKB:Q16539}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q16539}. Nucleus
CC {ECO:0000250|UniProtKB:Q16539}.
CC -!- PTM: Dually phosphorylated on Thr-180 and Tyr-182 by the MAP2Ks
CC MAP2K3/MKK3, MAP2K4/MKK4 and MAP2K6/MKK6 in response to inflammatory
CC cytokines, environmental stress or growth factors, which activates the
CC enzyme. Dual phosphorylation can also be mediated by TAB1-mediated
CC autophosphorylation. TCR engagement in T-cells also leads to Tyr-323
CC phosphorylation by ZAP70. Dephosphorylated and inactivated by DUPS1,
CC DUSP10 and DUSP16 (By similarity). PPM1D also mediates
CC dephosphorylation and inactivation of MAPK14 (By similarity).
CC {ECO:0000250, ECO:0000250|UniProtKB:Q16539}.
CC -!- PTM: Acetylated at Lys-53 and Lys-152 by KAT2B and EP300. Acetylation
CC at Lys-53 increases the affinity for ATP and enhances kinase activity.
CC Lys-53 and Lys-152 are deacetylated by HDAC3 (By similarity).
CC {ECO:0000250|UniProtKB:Q16539}.
CC -!- PTM: Ubiquitinated. Ubiquitination leads to degradation by the
CC proteasome pathway (By similarity). {ECO:0000250|UniProtKB:Q16539}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CMGC Ser/Thr
CC protein kinase family. MAP kinase subfamily. {ECO:0000305}.
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DR EMBL; AF100545; AAF36771.1; -; mRNA.
DR RefSeq; NP_001009065.1; NM_001009065.1.
DR AlphaFoldDB; Q95NE7; -.
DR SMR; Q95NE7; -.
DR STRING; 9598.ENSPTRP00000030915; -.
DR PaxDb; Q95NE7; -.
DR Ensembl; ENSPTRT00000097220; ENSPTRP00000087556; ENSPTRG00000018097.
DR GeneID; 450161; -.
DR KEGG; ptr:450161; -.
DR CTD; 1432; -.
DR VGNC; VGNC:7197; MAPK14.
DR eggNOG; KOG0660; Eukaryota.
DR GeneTree; ENSGT00940000155325; -.
DR HOGENOM; CLU_000288_181_1_1; -.
DR InParanoid; Q95NE7; -.
DR OMA; YTDLNPV; -.
DR TreeFam; TF105100; -.
DR BRENDA; 2.7.11.24; 4497.
DR Proteomes; UP000002277; Chromosome 6.
DR Bgee; ENSPTRG00000018097; Expressed in bone marrow and 20 other tissues.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004707; F:MAP kinase activity; ISS:UniProtKB.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IBA:GO_Central.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0035556; P:intracellular signal transduction; ISS:UniProtKB.
DR GO; GO:0038066; P:p38MAPK cascade; ISS:UniProtKB.
DR GO; GO:0045663; P:positive regulation of myoblast differentiation; ISS:UniProtKB.
DR GO; GO:1901741; P:positive regulation of myoblast fusion; ISS:UniProtKB.
DR GO; GO:0010831; P:positive regulation of myotube differentiation; ISS:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; IEA:InterPro.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; ISS:UniProtKB.
DR CDD; cd07877; STKc_p38alpha; 1.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR003527; MAP_kinase_CS.
DR InterPro; IPR008352; MAPK_p38-like.
DR InterPro; IPR038784; p38alpha.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR Pfam; PF00069; Pkinase; 1.
DR PRINTS; PR01773; P38MAPKINASE.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS01351; MAPK; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
PE 2: Evidence at transcript level;
KW Acetylation; Apoptosis; ATP-binding; Cytoplasm; Kinase; Nucleotide-binding;
KW Nucleus; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; Stress response; Transcription;
KW Transcription regulation; Transferase; Ubl conjugation.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:Q16539"
FT CHAIN 2..360
FT /note="Mitogen-activated protein kinase 14"
FT /id="PRO_0000186293"
FT DOMAIN 24..308
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT ACT_SITE 150
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 30..38
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 53
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 2
FT /note="N-acetylserine"
FT /evidence="ECO:0000250|UniProtKB:Q16539"
FT MOD_RES 2
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q16539"
FT MOD_RES 16
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q16539"
FT MOD_RES 53
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q16539"
FT MOD_RES 152
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q16539"
FT MOD_RES 180
FT /note="Phosphothreonine; by MAP2K3, MAP2K4, MAP2K6 and
FT autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q16539"
FT MOD_RES 182
FT /note="Phosphotyrosine; by MAP2K3, MAP2K4, MAP2K6 and
FT autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q16539"
FT MOD_RES 263
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q16539"
FT MOD_RES 323
FT /note="Phosphotyrosine; by ZAP70"
FT /evidence="ECO:0000250|UniProtKB:Q16539"
SQ SEQUENCE 360 AA; 41493 MW; 062EBC3E56683D14 CRC64;
MSQERPTFYR QELNKTIWEV PERYQNLSPV GSGAYGSVCA AFDTKTGLRV AVKKLSRPFQ
SIIHAKRTYR ELRLLKHMKH ENVIGLLDVF TPARSLEEFN DVYLVTHLMG ADLNNIVKCQ
KLTDDHVQFL IYQILRGLKY IHSADIIHRD LKPSNLAVNE DCELKILDFG LARHTDDEMT
GYVATRWYRA PEIMLNWMHY NQTVDIWSVG CIMAELLTGR TLFPGTDHIN QLQQIMRLTG
TPPAYLINRM PSHEARNYIQ SLTQMPKMNF ANVFIGANPL AVDLLEKMLV LDSDKRITAA
QALAHAYFAQ YHDPDDEPVA DPYDQSFESR DLLIDEWKSL TYDEVISFVP PPLDQEEMES
