ID MAPK5_HUMAN Reviewed; 473 AA. AC Q8IW41; B3KVA5; O60491; Q86X46; Q9BVX9; Q9UG86; DT 13-SEP-2004, integrated into UniProtKB/Swiss-Prot. DT 13-SEP-2004, sequence version 2. DT 24-JAN-2024, entry version 189. DE RecName: Full=MAP kinase-activated protein kinase 5; DE Short=MAPK-activated protein kinase 5; DE Short=MAPKAP kinase 5; DE Short=MAPKAP-K5; DE Short=MAPKAPK-5; DE Short=MK-5; DE Short=MK5; DE EC=2.7.11.1; DE AltName: Full=p38-regulated/activated protein kinase; DE Short=PRAK; GN Name=MAPKAPK5; Synonyms=PRAK; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 2), MUTAGENESIS OF THR-182, RP FUNCTION, TISSUE SPECIFICITY, PHOSPHORYLATION AT THR-182, AND ACTIVITY RP REGULATION. RC TISSUE=Placenta; RX PubMed=9628874; DOI=10.1093/emboj/17.12.3372; RA New L., Jiang Y., Zhao M., Liu K., Zhu W., Flood L.J., Kato Y., RA Parry G.C.N., Han J.; RT "PRAK, a novel protein kinase regulated by the p38 MAP kinase."; RL EMBO J. 17:3372-3384(1998). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Cervix, Pancreas, and Placenta; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 133-473 (ISOFORM 2). RC TISSUE=Brain; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [6] RP INTERACTION WITH SQSTM1, ACTIVITY REGULATION, AND SUBCELLULAR LOCATION. RX PubMed=10708586; DOI=10.1006/bbrc.2000.2333; RA Sudo T., Maruyama M., Osada H.; RT "p62 functions as a p38 MAP kinase regulator."; RL Biochem. Biophys. Res. Commun. 269:521-525(2000). RN [7] RP SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-212, MUTAGENESIS OF THR-182, RP AND MUTAGENESIS OF LYS-51; THR-182 AND SER-212. RX PubMed=12808055; DOI=10.1091/mbc.e02-08-0538; RA New L., Jiang Y., Han J.; RT "Regulation of PRAK subcellular location by p38 MAP kinases."; RL Mol. Biol. Cell 14:2603-2616(2003). RN [8] RP FUNCTION IN PHOSPHORYLATION OF HSPB1, AND INTERACTION WITH YWHAE. RX PubMed=17728103; DOI=10.1016/j.cellsig.2007.07.016; RA Tak H., Jang E., Kim S.B., Park J., Suk J., Yoon Y.S., Ahn J.K., Lee J.H., RA Joe C.O.; RT "14-3-3epsilon inhibits MK5-mediated cell migration by disrupting F-actin RT polymerization."; RL Cell. Signal. 19:2379-2387(2007). RN [9] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [10] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [11] RP FUNCTION IN PHOSPHORYLATION OF HSPB1. RX PubMed=19166925; DOI=10.1016/j.cellsig.2009.01.009; RA Kostenko S., Johannessen M., Moens U.; RT "PKA-induced F-actin rearrangement requires phosphorylation of Hsp27 by the RT MAPKAP kinase MK5."; RL Cell. Signal. 21:712-718(2009). RN [12] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-182, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [13] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-182 AND SER-354, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [14] RP VARIANTS [LARGE SCALE ANALYSIS] ILE-67 AND LYS-282. RX PubMed=17344846; DOI=10.1038/nature05610; RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G., RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., RA Futreal P.A., Stratton M.R.; RT "Patterns of somatic mutation in human cancer genomes."; RL Nature 446:153-158(2007). RN [15] RP FUNCTION IN PHOSPHORYLATION OF TP53. RX PubMed=17254968; DOI=10.1016/j.cell.2006.11.050; RA Sun P., Yoshizuka N., New L., Moser B.A., Li Y., Liao R., Xie C., Chen J., RA Deng Q., Yamout M., Dong M.Q., Frangou C.G., Yates J.R. III, Wright P.E., RA Han J.; RT "PRAK is essential for ras-induced senescence and tumor suppression."; RL Cell 128:295-308(2007). RN [16] RP FUNCTION IN PHOSPHORYLATION OF FOXO3, AUTOPHOSPHORYLATION, INDUCTION, AND RP MUTAGENESIS OF THR-182 AND LEU-337. RX PubMed=21329882; DOI=10.1016/j.molcel.2011.01.023; RA Kress T.R., Cannell I.G., Brenkman A.B., Samans B., Gaestel M., Roepman P., RA Burgering B.M., Bushell M., Rosenwald A., Eilers M.; RT "The MK5/PRAK kinase and Myc form a negative feedback loop that is RT disrupted during colorectal tumorigenesis."; RL Mol. Cell 41:445-457(2011). RN [17] RP REVIEW. RX PubMed=20227494; DOI=10.1016/j.cellsig.2010.03.002; RA Shiryaev A., Moens U.; RT "Mitogen-activated protein kinase p38 and MK2, MK3 and MK5: menage a trois RT or menage a quatre?"; RL Cell. Signal. 22:1185-1192(2010). RN [18] RP INVOLVEMENT IN NCFD. RX PubMed=33442026; DOI=10.1038/s41436-020-01052-2; RA Horn D., Fernandez-Nunez E., Gomez-Carmona R., Rivera-Barahona A., RA Nevado J., Schwartzmann S., Ehmke N., Lapunzina P., Otaify G.A., RA Temtamy S., Aglan M., Boschann F., Ruiz-Perez V.L.; RT "Biallelic truncating variants in MAPKAPK5 cause a new developmental RT disorder involving neurological, cardiac, and facial anomalies combined RT with synpolydactyly."; RL Genet. Med. 23:679-688(2021). CC -!- FUNCTION: Tumor suppressor serine/threonine-protein kinase involved in CC mTORC1 signaling and post-transcriptional regulation. Phosphorylates CC FOXO3, ERK3/MAPK6, ERK4/MAPK4, HSP27/HSPB1, p53/TP53 and RHEB. Acts as CC a tumor suppressor by mediating Ras-induced senescence and CC phosphorylating p53/TP53. Involved in post-transcriptional regulation CC of MYC by mediating phosphorylation of FOXO3: phosphorylation of FOXO3 CC leads to promote nuclear localization of FOXO3, enabling expression of CC miR-34b and miR-34c, 2 post-transcriptional regulators of MYC that bind CC to the 3'UTR of MYC transcript and prevent MYC translation. Acts as a CC negative regulator of mTORC1 signaling by mediating phosphorylation and CC inhibition of RHEB. Part of the atypical MAPK signaling via its CC interaction with ERK3/MAPK6 or ERK4/MAPK4: the precise role of the CC complex formed with ERK3/MAPK6 or ERK4/MAPK4 is still unclear, but the CC complex follows a complex set of phosphorylation events: upon CC interaction with atypical MAPK (ERK3/MAPK6 or ERK4/MAPK4), ERK3/MAPK6 CC (or ERK4/MAPK4) is phosphorylated and then mediates phosphorylation and CC activation of MAPKAPK5, which in turn phosphorylates ERK3/MAPK6 (or CC ERK4/MAPK4). Mediates phosphorylation of HSP27/HSPB1 in response to CC PKA/PRKACA stimulation, inducing F-actin rearrangement. CC {ECO:0000269|PubMed:17254968, ECO:0000269|PubMed:17728103, CC ECO:0000269|PubMed:19166925, ECO:0000269|PubMed:21329882, CC ECO:0000269|PubMed:9628874}. 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 at Thr-182 by CC p38-alpha/MAPK14, p38-beta/MAPK11, ERK2/MAPK1, ERK3/MAPK6, and CC ERK4/MAPK4. Activated by stress-related extracellular stimuli; such as CC H(2)O(2), arsenite, anisomycin TNF alpha and also PMA and the calcium CC ionophore A23187; but to a lesser extent. In vitro, activated by CC SQSTM1. Inhibited by diterpenoid alkaloid noroxoaconitine. CC {ECO:0000269|PubMed:10708586, ECO:0000269|PubMed:9628874}. CC -!- SUBUNIT: Interacts with ERK3/MAPK6 and ERK4/MAPK4 (via FRIEDE motif); CC the interaction is direct (By similarity). Interacts with YWHAE; the CC interaction prevents phosphorylation of HSP27/HSPB1 leading to disrupt CC F-actin polymerization. Interacts with SQSTM1. {ECO:0000250, CC ECO:0000269|PubMed:10708586, ECO:0000269|PubMed:17728103}. CC -!- INTERACTION: CC Q8IW41; Q15109: AGER; NbExp=6; IntAct=EBI-1201460, EBI-1646426; CC Q8IW41; P04792: HSPB1; NbExp=2; IntAct=EBI-1201460, EBI-352682; CC Q8IW41; Q16659: MAPK6; NbExp=9; IntAct=EBI-1201460, EBI-1384105; CC Q8IW41; P04637: TP53; NbExp=2; IntAct=EBI-1201460, EBI-366083; CC Q8IW41-2; Q16659: MAPK6; NbExp=6; IntAct=EBI-11958803, EBI-1384105; CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Translocates to the CC cytoplasm following phosphorylation and activation. Interaction with CC ERK3/MAPK6 or ERK4/MAPK4 and phosphorylation at Thr-182, activates the CC protein kinase activity, followed by translocation to the cytoplasm. CC Phosphorylation by PKA/PRKACA at Ser-115 also induces nuclear export. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q8IW41-1; Sequence=Displayed; CC Name=2; CC IsoId=Q8IW41-2; Sequence=VSP_011597; CC -!- TISSUE SPECIFICITY: Expressed ubiquitously. CC {ECO:0000269|PubMed:9628874}. CC -!- INDUCTION: Directly regulated by MYC: expression is activated by MYC, CC suggesting the existence of a feedback regulatory loop. CC {ECO:0000269|PubMed:21329882}. CC -!- PTM: Phosphorylated on Thr-182 ERK3/MAPK6 or ERK4/MAPK4; which is the CC regulatory phosphorylation site and is located on the T-loop/loop 12, CC leading to activation. Phosphorylation at Thr-182 by p38-alpha/MAPK14, CC p38-beta/MAPK11 is subject to debate. Phosphorylated at Ser-115 by CC PKA/PRKACA, leading to localization to the cytoplasm. CC Autophosphorylated (By similarity). {ECO:0000250}. CC -!- DISEASE: Neurocardiofaciodigital syndrome (NCFD) [MIM:619869]: An CC autosomal recessive syndrome characterized by severe developmental CC delay, variable brain anomalies, congenital heart defects, dysmorphic CC facial features, and a distinctive type of synpolydactyly with a CC supernumerary hypoplastic digit between the fourth and fifth digits of CC the hands and/or feet. Other features include eye abnormalities, CC hearing impairment, and electroencephalogram anomalies. CC {ECO:0000269|PubMed:33442026}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CAMK Ser/Thr CC protein kinase family. {ECO:0000305}. CC -!- CAUTION: The role of p38 MAPK kinases is unclear in phosphorylation and CC activation of MAPKAPK5. According to some reports, it interacts and is CC phosphorylated by p38-alpha/MAPK14 and p38-beta/MAPK11 (PubMed:9628874, CC PubMed:12808055). According to other reports, it is not activated by CC p38-alpha/MAPK14 and p38-beta/MAPK11. An explanation for these CC discrepancies, might be that the interaction with p38 MAPK kinases is CC weak and occurs only under specific conditions. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF032437; AAC39863.1; -; Genomic_DNA. DR EMBL; AK122767; BAG53717.1; -; mRNA. DR EMBL; CH471054; EAW97981.1; -; Genomic_DNA. DR EMBL; BC000833; AAH00833.1; -; mRNA. DR EMBL; BC041049; AAH41049.1; -; mRNA. DR EMBL; BC047284; AAH47284.2; -; mRNA. DR EMBL; AL110301; CAB53747.1; -; mRNA. DR CCDS; CCDS44975.1; -. [Q8IW41-1] DR CCDS; CCDS44976.1; -. [Q8IW41-2] DR PIR; T34519; T34519. DR RefSeq; NP_003659.2; NM_003668.3. [Q8IW41-2] DR RefSeq; NP_620777.1; NM_139078.2. [Q8IW41-1] DR AlphaFoldDB; Q8IW41; -. DR SMR; Q8IW41; -. DR BioGRID; 114120; 48. DR CORUM; Q8IW41; -. DR IntAct; Q8IW41; 27. DR MINT; Q8IW41; -. DR STRING; 9606.ENSP00000449381; -. DR BindingDB; Q8IW41; -. DR ChEMBL; CHEMBL3094; -. DR DrugBank; DB12010; Fostamatinib. DR GuidetoPHARMACOLOGY; 2096; -. DR iPTMnet; Q8IW41; -. DR PhosphoSitePlus; Q8IW41; -. DR BioMuta; MAPKAPK5; -. DR DMDM; 52000829; -. DR EPD; Q8IW41; -. DR jPOST; Q8IW41; -. DR MassIVE; Q8IW41; -. DR MaxQB; Q8IW41; -. DR PaxDb; 9606-ENSP00000449381; -. DR PeptideAtlas; Q8IW41; -. DR ProteomicsDB; 70805; -. [Q8IW41-1] DR ProteomicsDB; 70806; -. [Q8IW41-2] DR Pumba; Q8IW41; -. DR Antibodypedia; 3873; 759 antibodies from 40 providers. DR DNASU; 8550; -. DR Ensembl; ENST00000550735.7; ENSP00000449667.2; ENSG00000089022.15. [Q8IW41-2] DR Ensembl; ENST00000551404.7; ENSP00000449381.2; ENSG00000089022.15. [Q8IW41-1] DR GeneID; 8550; -. DR KEGG; hsa:8550; -. DR MANE-Select; ENST00000550735.7; ENSP00000449667.2; NM_003668.4; NP_003659.2. [Q8IW41-2] DR UCSC; uc001tta.5; human. [Q8IW41-1] DR AGR; HGNC:6889; -. DR CTD; 8550; -. DR DisGeNET; 8550; -. DR GeneCards; MAPKAPK5; -. DR HGNC; HGNC:6889; MAPKAPK5. DR HPA; ENSG00000089022; Low tissue specificity. DR MalaCards; MAPKAPK5; -. DR MIM; 606723; gene. DR MIM; 619869; phenotype. DR neXtProt; NX_Q8IW41; -. DR OpenTargets; ENSG00000089022; -. DR PharmGKB; PA30633; -. DR VEuPathDB; HostDB:ENSG00000089022; -. DR eggNOG; KOG0604; Eukaryota. DR GeneTree; ENSGT00940000154089; -. DR HOGENOM; CLU_000288_63_0_1; -. DR InParanoid; Q8IW41; -. DR OMA; QTASHES; -. DR OrthoDB; 1121238at2759; -. DR PhylomeDB; Q8IW41; -. DR TreeFam; TF312891; -. DR PathwayCommons; Q8IW41; -. DR Reactome; R-HSA-2559580; Oxidative Stress Induced Senescence. DR Reactome; R-HSA-5687128; MAPK6/MAPK4 signaling. DR Reactome; R-HSA-6804756; Regulation of TP53 Activity through Phosphorylation. DR SignaLink; Q8IW41; -. DR SIGNOR; Q8IW41; -. DR BioGRID-ORCS; 8550; 22 hits in 1188 CRISPR screens. DR ChiTaRS; MAPKAPK5; human. DR GeneWiki; MAPKAPK5; -. DR GenomeRNAi; 8550; -. DR Pharos; Q8IW41; Tchem. DR PRO; PR:Q8IW41; -. DR Proteomes; UP000005640; Chromosome 12. DR RNAct; Q8IW41; Protein. DR Bgee; ENSG00000089022; Expressed in rectum and 185 other cell types or tissues. DR ExpressionAtlas; Q8IW41; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IBA:GO_Central. DR GO; GO:0032991; C:protein-containing complex; IEA:Ensembl. DR GO; GO:0032156; C:septin cytoskeleton; IEA:Ensembl. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0009931; F:calcium-dependent protein serine/threonine kinase activity; IBA:GO_Central. DR GO; GO:0005516; F:calmodulin binding; IBA:GO_Central. DR GO; GO:0004683; F:calmodulin-dependent protein kinase activity; IBA:GO_Central. DR GO; GO:0004708; F:MAP kinase kinase activity; TAS:ProtInc. DR GO; GO:0051019; F:mitogen-activated protein kinase binding; IBA:GO_Central. DR GO; GO:0002039; F:p53 binding; IDA:UniProtKB. DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA. DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB. DR GO; GO:0090398; P:cellular senescence; TAS:Reactome. DR GO; GO:0032007; P:negative regulation of TOR signaling; ISS:UniProtKB. DR GO; GO:0060999; P:positive regulation of dendritic spine development; IEA:Ensembl. DR GO; GO:0051973; P:positive regulation of telomerase activity; IMP:BHF-UCL. DR GO; GO:1904355; P:positive regulation of telomere capping; IMP:BHF-UCL. DR GO; GO:0032212; P:positive regulation of telomere maintenance via telomerase; IMP:BHF-UCL. DR GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB. DR GO; GO:0007265; P:Ras protein signal transduction; IDA:UniProtKB. DR GO; GO:1901796; P:regulation of signal transduction by p53 class mediator; TAS:Reactome. DR GO; GO:0006417; P:regulation of translation; IDA:UniProtKB. DR GO; GO:0007165; P:signal transduction; TAS:ProtInc. DR GO; GO:0090400; P:stress-induced premature senescence; IDA:UniProtKB. DR CDD; cd14171; STKc_MAPKAPK5; 1. DR Gene3D; 4.10.1170.10; MAP kinase activated protein kinase 2; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR027442; MAPKAPK_C. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR008271; Ser/Thr_kinase_AS. DR PANTHER; PTHR24349:SF179; MAP KINASE-ACTIVATED PROTEIN KINASE 5; 1. DR PANTHER; PTHR24349; SERINE/THREONINE-PROTEIN KINASE; 1. DR Pfam; PF00069; Pkinase; 1. DR SMART; SM00220; S_TKc; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1. DR Genevisible; Q8IW41; HS. PE 1: Evidence at protein level; KW Alternative splicing; ATP-binding; Coiled coil; Cytoplasm; Kinase; KW Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome; KW Serine/threonine-protein kinase; Transferase; Tumor suppressor. FT CHAIN 1..473 FT /note="MAP kinase-activated protein kinase 5" FT /id="PRO_0000086296" FT DOMAIN 22..304 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT COILED 409..440 FT /evidence="ECO:0000255" FT ACT_SITE 148 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, FT ECO:0000255|PROSITE-ProRule:PRU10027" FT BINDING 28..36 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 51 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT MOD_RES 115 FT /note="Phosphoserine; by PKA" FT /evidence="ECO:0000250|UniProtKB:O54992" FT MOD_RES 182 FT /note="Phosphothreonine; by MAPK11, MAPK14, MAPK4, MAPK6 FT and PKA" FT /evidence="ECO:0000269|PubMed:9628874, FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:23186163" FT MOD_RES 212 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:12808055" FT MOD_RES 354 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT VAR_SEQ 407..408 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039, FT ECO:0000303|PubMed:15489334, ECO:0000303|PubMed:17974005" FT /id="VSP_011597" FT VARIANT 67 FT /note="M -> I (in dbSNP:rs34132040)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_040758" FT VARIANT 282 FT /note="R -> K (in dbSNP:rs34843470)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_040759" FT MUTAGEN 51 FT /note="K->M: Kinase defective mutant, abolishes activity." FT /evidence="ECO:0000269|PubMed:12808055" FT MUTAGEN 182 FT /note="T->A: No p38-beta/MAPK11-induced activation." FT /evidence="ECO:0000269|PubMed:12808055, FT ECO:0000269|PubMed:21329882, ECO:0000269|PubMed:9628874" FT MUTAGEN 182 FT /note="T->D: Mimicks phosphorylation state and induces FT constitutive protein kinase activity." FT /evidence="ECO:0000269|PubMed:12808055, FT ECO:0000269|PubMed:21329882, ECO:0000269|PubMed:9628874" FT MUTAGEN 212 FT /note="S->D: Mimicks phosphorylation state and displays a FT slightly higher protein kinase activity." FT /evidence="ECO:0000269|PubMed:12808055" FT MUTAGEN 337 FT /note="L->G: Induces constitutive protein kinase activity." FT /evidence="ECO:0000269|PubMed:21329882" FT CONFLICT 273 FT /note="I -> T (in Ref. 5; CAB53747)" FT /evidence="ECO:0000305" FT CONFLICT 291 FT /note="E -> R (in Ref. 1; AAC39863)" FT /evidence="ECO:0000305" SQ SEQUENCE 473 AA; 54220 MW; F3D9DDC83CC0C49D CRC64; MSEESDMDKA IKETSILEEY SINWTQKLGA GISGPVRVCV KKSTQERFAL KILLDRPKAR NEVRLHMMCA THPNIVQIIE VFANSVQFPH ESSPRARLLI VMEMMEGGEL FHRISQHRHF TEKQASQVTK QIALALRHCH LLNIAHRDLK PENLLFKDNS LDAPVKLCDF GFAKIDQGDL MTPQFTPYYV APQVLEAQRR HQKEKSGIIP TSPTPYTYNK SCDLWSLGVI IYVMLCGYPP FYSKHHSRTI PKDMRRKIMT GSFEFPEEEW SQISEMAKDV VRKLLKVKPE ERLTIEGVLD HPWLNSTEAL DNVLPSAQLM MDKAVVAGIQ QAHAEQLANM RIQDLKVSLK PLHSVNNPIL RKRKLLGTKP KDSVYIHDHE NGAEDSNVAL EKLRDVIAQC ILPQAGKGEN EDEKLNEVMQ EAWKYNRECK LLRDTLQSFS WNGRGFTDKV DRLKLAEIVK QVIEEQTTSH ESQ //