BioPAX pathway converted from "Active p38 MAPK phosphorylates MAPKAPK2 or 3 " in the Reactome database. LEFT-TO-RIGHT 2.7.12.1 Active p38 MAPK phosphorylates MAPKAPK2 or 3 Human p38 MAPK alpha forms a complex with MK2 even when the signaling pathway is not activated. This heterodimer is found mainly in the nucleus. The crystal structure of the unphosphorylated p38alpha-MK2 heterodimer was determined. The C-terminal regulatory domain of MK2 binds in the docking groove of p38 MAPK alpha, and the ATP-binding sites of both kinases are at the heterodimer interface (ter Haar et al. 2007).<p>Upon activation, p38 MAPK alpha activates MK2 by phosphorylating Thr-222, Ser-272, and Thr-334 (Ben-Levy et al. 1995). <p>The phosphorylation of MK2 at Thr-334 attenuates the affinity of the binary complex MK2:p38 alpha by an order of magnitude and leads to a large conformational change of an autoinhibitory domain in MK2. This conformational change unmasks not only the MK2 substrate-binding site but also the MK2 nuclear export signal (NES) thus leading to the MK2:p38 alpha translocation from the nucleus to the cytoplasm. Cytoplasmic active MK2 then phosphorylates downstream targets such as the heat-shock protein HSP27 and tristetraprolin (TTP) (Meng et al. 2002, Lukas et al. 2004, White et al. 2007).<p>MAPKAPK (MAPK-activated protein) kinase 3 (MK3, also known as 3pK) has been identified as the second p38 MAPK-activated kinase that is stimulated by different stresses (McLaughlin et al. 1996; Sithanandam et al. 1996; reviewed in Gaestel 2006). MK3 shows 75% sequence identity to MK2 and, like MK2, is activated by p38 MAPK alpha and p38 MAPK beta. MK3 phosphorylates peptide substrates with kinetic constants similar to MK2 and phosphorylates the same serine residues in HSP27 at the same relative rates as MK2 (Clifton et al. 1996) indicating an identical phosphorylation-site consensus sequence. Hence, it is assumed that its substrate spectrum is either identical to or at least overlapping with MK2. Authored: Shamovsky, V, 2009-09-22 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 phospho -p38 MAPK : MAPKAPK 2 or MAPKAPK3 Reactome DB_ID: 442905 nucleoplasm GENE ONTOLOGY GO:0005654 Converted from EntitySet in Reactome MAPKAPK2 and/or MAPKAPK3 Reactome DB_ID: 442936 MAPKAPK2 Reactome DB_ID: 442914 ENSEMBL:ENSGALP00000001295 MAPKAPK2 MAPKAPK2 Gallus gallus NCBI Taxonomy 9031 ENSEMBL ENSGALP00000001295 Reactome Database ID Release 83 442914 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442914 Reactome R-GGA-442914 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-442914.1 Reactome http://www.reactome.org MAPKAPK3 Reactome DB_ID: 442931 ENSEMBL:ENSGALP00000003578 MAPKAPK3 MAPKAPK3 ENSEMBL ENSGALP00000003578 Reactome Database ID Release 83 442931 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442931 Reactome R-GGA-442931 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-442931.1 Reactome Database ID Release 83 442936 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442936 Reactome R-GGA-442936 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-442936.1 1 Converted from EntitySet in Reactome phospho_p38 MAP kinase Reactome DB_ID: 442851 phosphorylated MAPK11 Reactome DB_ID: 571401 UniProt:Q5ZIK8 RCJMB04_25f21 RCJMB04_25f21 CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. UniProt Q5ZIK8 180 EQUAL O-phospho-L-threonine MOD MOD:00047 182 EQUAL O4'-phospho-L-tyrosine MOD MOD:00048 1 EQUAL 361 EQUAL Reactome Database ID Release 83 571401 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=571401 Reactome R-GGA-571401 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-571401.1 p38 MAP kinase phosphorylated MAPK12 Reactome DB_ID: 571407 ENSEMBL:ENSGALP00000014011 MAPK12 MAPK12 ENSEMBL ENSGALP00000014011 Reactome Database ID Release 83 571407 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=571407 Reactome R-GGA-571407 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-571407.1 phosphorylated MAPK13 Reactome DB_ID: 571406 ENSEMBL:ENSGALP00000001204 MAPK13 MAPK13 ENSEMBL ENSGALP00000001204 Reactome Database ID Release 83 571406 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=571406 Reactome R-GGA-571406 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-571406.1 phosphorylated MAPK14 Reactome DB_ID: 571404 ENSEMBL:ENSGALP00000001201 MAPK14 MAPK14 ENSEMBL ENSGALP00000001201 Reactome Database ID Release 83 571404 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=571404 Reactome R-GGA-571404 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-571404.1 Reactome Database ID Release 83 442851 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442851 Reactome R-GGA-442851 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-442851.1 1 Reactome Database ID Release 83 442905 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442905 Reactome R-GGA-442905 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-442905.1 ATP Adenosine 5'-triphosphate ATP(4-) Reactome DB_ID: 29358 ATP(4-) [ChEBI:30616] ATP(4-) ATP atp Adenosine 5'-triphosphate ChEBI CHEBI:30616 Reactome Database ID Release 83 29358 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29358 Reactome R-ALL-29358 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29358.3 COMPOUND C00002 additional information MI MI:0361 3 phospho -p38 MAPK : phospho- MAPKAPK 2 or phospho MAPKAPK3 Reactome DB_ID: 442915 Converted from EntitySet in Reactome phospho MAPKAPK2 and/or phospho MAPKAPK3 Reactome DB_ID: 442949 phosphorylated MAPKAPK2 Reactome DB_ID: 442932 O-phospho-L-serine MOD MOD:00046 Reactome Database ID Release 83 442932 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442932 Reactome R-GGA-442932 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-442932.1 phosphorylated MAPKAPK3 Reactome DB_ID: 442924 Reactome Database ID Release 83 442924 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442924 Reactome R-GGA-442924 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-442924.1 Reactome Database ID Release 83 442949 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442949 Reactome R-GGA-442949 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-442949.1 1 1 Reactome Database ID Release 83 442915 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442915 Reactome R-GGA-442915 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-442915.1 ADP Adenosine 5'-diphosphate ADP(3-) Reactome DB_ID: 113582 ADP(3-) [ChEBI:456216] ADP(3-) ADP 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP trianion ChEBI CHEBI:456216 Reactome Database ID Release 83 113582 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113582 Reactome R-ALL-113582 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113582.3 COMPOUND C00008 3 ACTIVATION activeUnit: #Protein4 GENE ONTOLOGY GO:0004712 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity Reactome Database ID Release 83 442864 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442864 Reactome Database ID Release 83 442913 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442913 Reactome R-GGA-442913 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-442913.2 17255097 Pubmed 2007 Crystal structure of the p38 alpha-MAPKAP kinase 2 heterodimer Ter Haar, E Prabhakar, P Liu, X Lepre, C J Biol Chem 282:9733-9 15287722 Pubmed 2004 Catalysis and function of the p38 alpha.MK2a signaling complex Lukas, SM Kroe, RR Wildeson, J Peet, GW Frego, L Davidson, W Ingraham, RH Pargellis, CA Labadia, ME Werneburg, BG Biochemistry 43:9950-60 17395714 Pubmed 2007 Molecular basis of MAPK-activated protein kinase 2:p38 assembly White, A Pargellis, CA Studts, JM Werneburg, BG Farmer BT, 2nd Proc Natl Acad Sci U S A 104:6353-8 8846784 Pubmed 1995 Identification of novel phosphorylation sites required for activation of MAPKAP kinase-2 Ben-Levy, R Leighton, IA Doza, YN Attwood, P Morrice, N Marshall, CJ Cohen, P EMBO J 14:5920-30 12171911 Pubmed 2002 Structure of mitogen-activated protein kinase-activated protein (MAPKAP) kinase 2 suggests a bifunctional switch that couples kinase activation with nuclear export Meng, W Swenson, LL Fitzgibbon, MJ Hayakawa, K Ter Haar, E Behrens, AE Fulghum, JR Lippke, JA J Biol Chem 277:37401-5 INHIBITION Reactome Database ID Release 83 442897 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442897 Reactome R-GGA-442897 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-442897.1 Converted from EntitySet in Reactome MAPK phosphatases dual specificity phosphatases Reactome DB_ID: 442886 MKP1 Dual specificity protein phosphatase 1 Reactome DB_ID: 442888 UniProt:O42253 Dual specificity protein phosphatase 1 Dual specificity protein phosphatase 1 MKP1 UniProt O42253 1 EQUAL 353 EQUAL Reactome Database ID Release 83 442888 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442888 Reactome R-GGA-442888 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-442888.1 MKP2 DUSP4 Reactome DB_ID: 442850 UniProt:Q9PW71 DUSP4 DUSP4 MKP2 FUNCTION Regulates mitogenic signal transduction by dephosphorylating both Thr and Tyr residues on MAP kinases ERK1 and ERK2.SIMILARITY Belongs to the protein-tyrosine phosphatase family. Non-receptor class dual specificity subfamily. UniProt Q9PW71 1 EQUAL 375 EQUAL Reactome Database ID Release 83 442850 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442850 Reactome R-GGA-442850 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-442850.1 MKP3 DUSP6 Reactome DB_ID: 442887 UniProt:Q7T2L9 MKP3 MKP3 dual specificity phosphatase 6 UniProt Q7T2L9 1 EQUAL 382 EQUAL Reactome Database ID Release 83 442887 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442887 Reactome R-GGA-442887 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-442887.1 MKP5 DUSP10 Reactome DB_ID: 442877 UniProt:Q5ZJF8 Dual specificity protein phosphatase 10 Dual specificity protein phosphatase 10 RCJMB04_18i8 UniProt Q5ZJF8 1 EQUAL 478 EQUAL Reactome Database ID Release 83 442877 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442877 Reactome R-GGA-442877 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-442877.1 DUSP16 Reactome DB_ID: 442935 ENSEMBL:ENSGALP00000001453 DUSP16 DUSP16 ENSEMBL ENSGALP00000001453 Reactome Database ID Release 83 442935 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442935 Reactome R-GGA-442935 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-442935.1 DUSP3 dual specificity phosphatase 3 Reactome DB_ID: 442882 ENSEMBL:ENSGALP00000016127 DUSP3 DUSP3 ENSEMBL ENSGALP00000016127 Reactome Database ID Release 83 442882 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442882 Reactome R-GGA-442882 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-442882.1 DUSP5 Reactome DB_ID: 442941 ENSEMBL:ENSGALP00000013956 dual specificity phosphatase 5 dual specificity phosphatase 5 DUSP5 ENSEMBL ENSGALP00000013956 Reactome Database ID Release 83 442941 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442941 Reactome R-GGA-442941 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-442941.1 DUSP8 Reactome DB_ID: 442917 ENSEMBL:ENSGALP00000010737 DUSP8 DUSP8 ENSEMBL ENSGALP00000010737 Reactome Database ID Release 83 442917 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442917 Reactome R-GGA-442917 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-442917.1 MKP6 DUSP14 Reactome DB_ID: 442874 ENSEMBL:ENSGALP00000008741 DUSP14 DUSP14 dual specificity phosphatase 14 ENSEMBL ENSGALP00000008741 Reactome Database ID Release 83 442874 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442874 Reactome R-GGA-442874 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-442874.1 Reactome Database ID Release 83 442886 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442886 Reactome R-GGA-442886 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-442886.1