MAPK2_RABIT
ID MAPK2_RABIT Reviewed; 366 AA.
AC P49139; G1T708;
DT 01-FEB-1996, integrated into UniProtKB/Swiss-Prot.
DT 25-JAN-2012, sequence version 2.
DT 03-AUG-2022, entry version 122.
DE RecName: Full=MAP kinase-activated protein kinase 2;
DE Short=MAPK-activated protein kinase 2;
DE Short=MAPKAP kinase 2;
DE Short=MAPKAP-K2;
DE Short=MAPKAPK-2;
DE Short=MK-2;
DE Short=MK2;
DE EC=2.7.11.1;
DE Flags: Fragment;
GN Name=MAPKAPK2;
OS Oryctolagus cuniculus (Rabbit).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Lagomorpha; Leporidae; Oryctolagus.
OX NCBI_TaxID=9986;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Thorbecke;
RG The Genome Sequencing Platform;
RA Di Palma F., Heiman D., Young S., Gnerre S., Johnson J., Lander E.S.,
RA Lindblad-Toh K.;
RT "Genome Sequence of Oryctolagus cuniculus (European rabbit).";
RL Submitted (AUG-2009) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-256.
RC STRAIN=New Zealand white; TISSUE=Skeletal muscle;
RX PubMed=8280084; DOI=10.1042/bj2960843;
RA Stokoe D., Caudwell B., Cohen P.T.W., Cohen P.;
RT "The substrate specificity and structure of mitogen-activated protein (MAP)
RT kinase-activated protein kinase-2.";
RL Biochem. J. 296:843-849(1993).
RN [3]
RP FUNCTION IN PHOSPHORYLATION OF HSPB1.
RX PubMed=1332886; DOI=10.1016/0014-5793(92)81216-9;
RA Stokoe D., Engel K., Campbell D.G., Cohen P., Gaestel M.;
RT "Identification of MAPKAP kinase 2 as a major enzyme responsible for the
RT phosphorylation of the small mammalian heat shock proteins.";
RL FEBS Lett. 313:307-313(1992).
RN [4]
RP PARTIAL PROTEIN SEQUENCE, FUNCTION, AND PHOSPHORYLATION AT THR-300.
RC STRAIN=New Zealand white;
RX PubMed=1327754; DOI=10.1002/j.1460-2075.1992.tb05492.x;
RA Stokoe D., Campbell D.G., Nakielny S., Hidaka H., Leevers S.J.,
RA Marshall C., Cohen P.;
RT "MAPKAP kinase-2; a novel protein kinase activated by mitogen-activated
RT protein kinase.";
RL EMBO J. 11:3985-3994(1992).
CC -!- FUNCTION: Stress-activated serine/threonine-protein kinase involved in
CC cytokine production, endocytosis, reorganization of the cytoskeleton,
CC cell migration, cell cycle control, chromatin remodeling, DNA damage
CC response and transcriptional regulation. Following stress, it is
CC phosphorylated and activated by MAP kinase p38-alpha/MAPK14, leading to
CC phosphorylation of substrates. Phosphorylates serine in the peptide
CC sequence, Hyd-X-R-X(2)-S, where Hyd is a large hydrophobic residue.
CC Phosphorylates ALOX5, CDC25B, CDC25C, CEP131, ELAVL1, HNRNPA0,
CC HSP27/HSPB1, KRT18, KRT20, LIMK1, LSP1, PABPC1, PARN, PDE4A, RCSD1,
CC RPS6KA3, TAB3 and TTP/ZFP36. Phosphorylates HSF1; leading to the
CC interaction with HSP90 proteins and inhibiting HSF1 homotrimerization,
CC DNA-binding and transactivation activities (By similarity). Mediates
CC phosphorylation of HSP27/HSPB1 in response to stress, leading to
CC dissociation of HSP27/HSPB1 from large small heat-shock protein (sHsps)
CC oligomers and impairment of their chaperone activities and ability to
CC protect against oxidative stress effectively. Involved in inflammatory
CC response by regulating tumor necrosis factor (TNF) and IL6 production
CC post-transcriptionally: acts by phosphorylating AU-rich elements
CC (AREs)-binding proteins ELAVL1, HNRNPA0, PABPC1 and TTP/ZFP36, leading
CC to regulate the stability and translation of TNF and IL6 mRNAs.
CC Phosphorylation of TTP/ZFP36, a major post-transcriptional regulator of
CC TNF, promotes its binding to 14-3-3 proteins and reduces its ARE mRNA
CC affinity leading to inhibition of dependent degradation of ARE-
CC containing transcripts. Phosphorylates CEP131 in response to cellular
CC stress following ultraviolet irradiation which promotes binding of
CC CEP131 to 14-3-3 proteins and inhibits formation of novel centriolar
CC satellites (By similarity). Also involved in late G2/M checkpoint
CC following DNA damage through a process of post-transcriptional mRNA
CC stabilization: following DNA damage, relocalizes from nucleus to
CC cytoplasm and phosphorylates HNRNPA0 and PARN, leading to stabilization
CC of GADD45A mRNA. Involved in toll-like receptor signaling pathway (TLR)
CC in dendritic cells: required for acute TLR-induced macropinocytosis by
CC phosphorylating and activating RPS6KA3. {ECO:0000250|UniProtKB:P49137,
CC ECO:0000269|PubMed:1327754, ECO:0000269|PubMed:1332886}.
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=2.7.11.1;
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=2.7.11.1;
CC -!- ACTIVITY REGULATION: Activated following phosphorylation by p38-
CC alpha/MAPK14 following various stresses. Inhibited following
CC sumoylation. Specifically inhibited by pyrrolopyridine inhibitors (By
CC similarity). {ECO:0000250}.
CC -!- SUBUNIT: Heterodimer with p38-alpha/MAPK14; this heterodimer forms a
CC stable complex: molecules are positioned 'face to face' so that the
CC ATP-binding sites of both kinases are at the heterodimer interface.
CC Interacts with PHC2. Interacts with HSF1.
CC {ECO:0000250|UniProtKB:P49137}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:P49137}. Nucleus
CC {ECO:0000250|UniProtKB:P49137}. Note=Phosphorylation and subsequent
CC activation releases the autoinhibitory helix, resulting in the export
CC from the nucleus into the cytoplasm. {ECO:0000250|UniProtKB:P49137}.
CC -!- PTM: Sumoylation inhibits the protein kinase activity.
CC {ECO:0000250|UniProtKB:P49137}.
CC -!- PTM: Phosphorylated and activated by MAP kinase p38-alpha/MAPK14 at
CC Thr-188, Ser-238 and Thr-300. {ECO:0000305|PubMed:1327754}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CAMK Ser/Thr
CC protein kinase family. {ECO:0000305}.
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DR EMBL; X75345; CAA53093.1; -; mRNA.
DR EMBL; AAGW02025411; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR PIR; S39794; S39794.
DR AlphaFoldDB; P49139; -.
DR BMRB; P49139; -.
DR SMR; P49139; -.
DR STRING; 9986.ENSOCUP00000012250; -.
DR iPTMnet; P49139; -.
DR eggNOG; KOG0604; Eukaryota.
DR InParanoid; P49139; -.
DR Proteomes; UP000001811; Unplaced.
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:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; ISS:UniProtKB.
DR GO; GO:0070935; P:3'-UTR-mediated mRNA stabilization; ISS:UniProtKB.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; ISS:UniProtKB.
DR GO; GO:0006954; P:inflammatory response; ISS:UniProtKB.
DR GO; GO:0044351; P:macropinocytosis; ISS:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; IEA:InterPro.
DR GO; GO:0032675; P:regulation of interleukin-6 production; ISS:UniProtKB.
DR GO; GO:0032680; P:regulation of tumor necrosis factor production; ISS:UniProtKB.
DR GO; GO:0034097; P:response to cytokine; ISS:UniProtKB.
DR GO; GO:0032496; P:response to lipopolysaccharide; ISS:UniProtKB.
DR GO; GO:0002224; P:toll-like receptor signaling pathway; ISS:UniProtKB.
DR Gene3D; 4.10.1170.10; -; 1.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR027442; MAPKAPK_C.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW ATP-binding; Cytoplasm; Direct protein sequencing; DNA damage;
KW Isopeptide bond; Kinase; Nucleotide-binding; Nucleus; Phosphoprotein;
KW Reference proteome; Serine/threonine-protein kinase; Transferase;
KW Ubl conjugation.
FT CHAIN <1..366
FT /note="MAP kinase-activated protein kinase 2"
FT /id="PRO_0000086290"
FT DOMAIN 30..291
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 294..330
FT /note="Autoinhibitory helix"
FT /evidence="ECO:0000250"
FT REGION 332..356
FT /note="p38 MAPK-binding site"
FT /evidence="ECO:0000250"
FT MOTIF 322..331
FT /note="Nuclear export signal (NES)"
FT /evidence="ECO:0000250"
FT MOTIF 337..340
FT /note="Bipartite nuclear localization signal 1"
FT /evidence="ECO:0000250"
FT MOTIF 351..355
FT /note="Bipartite nuclear localization signal 2"
FT /evidence="ECO:0000250"
FT ACT_SITE 152
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 36..44
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 59
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 105..107
FT /ligand="staurosporine"
FT /ligand_id="ChEBI:CHEBI:57491"
FT /evidence="ECO:0000250"
FT MOD_RES 188
FT /note="Phosphothreonine; by MAPK14"
FT /evidence="ECO:0000250|UniProtKB:P49137"
FT MOD_RES 238
FT /note="Phosphoserine; by MAPK14"
FT /evidence="ECO:0000250|UniProtKB:P49137"
FT MOD_RES 294
FT /note="Phosphoserine; by autocatalysis"
FT /evidence="ECO:0000250"
FT MOD_RES 300
FT /note="Phosphothreonine; by MAPK14"
FT /evidence="ECO:0000269|PubMed:1327754"
FT CROSSLNK 319
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO)"
FT /evidence="ECO:0000250"
FT CONFLICT 111
FT /note="E -> L (in Ref. 2; CAA53093)"
FT /evidence="ECO:0000305"
FT CONFLICT 315
FT /note="W -> G (in Ref. 4; AA sequence)"
FT /evidence="ECO:0000305"
FT NON_TER 1
SQ SEQUENCE 366 AA; 42124 MW; F1F86EDE08C42C34 CRC64;
PPPPPPQQFP QFHVRSGLQI KKNAIIDDYK VTSQVLGLGI NGKVLQIFSK KTQEKFALKM
LQDCPKARRE VELHWRASQC PHIVRIVDVY ENLYAGRKCL LIVMECLDGG ELFSRIQDRG
DQAFTEREAS EIMKSIGEAI QYLHSINIAH RDVKPENLLY TSKRPKAILK LTDFGFAKET
TSHNSLTTPC YTPYYVAPEV LGPEKYDKSC DMWSLGVIMY ILLCGYPPFY SNHGLAISPG
MKTRIRMGQY EFPNPEWSEV SEEVKMLIRN LLKTEPTQRM TITEFMNHPW IMQSTKVPQT
PLHTSRVLKE DKERWEDVKE EMTSALATMR VDYEQIKIKK IEDASNPLLL KRRKKARALE
AAALAH
