M3K2_MOUSE
ID M3K2_MOUSE Reviewed; 619 AA.
AC Q61083;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 29-MAR-2005, sequence version 2.
DT 03-AUG-2022, entry version 179.
DE RecName: Full=Mitogen-activated protein kinase kinase kinase 2;
DE EC=2.7.11.25;
DE AltName: Full=MAPK/ERK kinase kinase 2;
DE Short=MEK kinase 2;
DE Short=MEKK 2;
GN Name=Map3k2; Synonyms=Mekk2;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Brain;
RX PubMed=8621389; DOI=10.1074/jbc.271.10.5361;
RA Blank J.L., Gerwins P., Elliott E.M., Sather S., Johnson G.L.;
RT "Molecular cloning of mitogen-activated protein/ERK kinase kinases (MEKK) 2
RT and 3. Regulation of sequential phosphorylation pathways involving mitogen-
RT activated protein kinase and c-Jun kinase.";
RL J. Biol. Chem. 271:5361-5368(1996).
RN [2]
RP INTERACTION WITH PKN2.
RX PubMed=10818102; DOI=10.1074/jbc.m003148200;
RA Sun W., Vincent S., Settleman J., Johnson G.L.;
RT "MEK kinase 2 binds and activates protein kinase C-related kinase 2.
RT Bifurcation of kinase regulatory pathways at the level of an MAPK kinase
RT kinase.";
RL J. Biol. Chem. 275:24421-24428(2000).
RN [3]
RP FUNCTION, AUTOPHOSPHORYLATION, AND MUTAGENESIS OF PHE-571; ILE-573;
RP THR-575; GLN-576; PRO-577; PRO-580; LEU-582; PRO-583 AND VAL-586.
RX PubMed=12659851; DOI=10.1016/s0006-291x(03)00387-5;
RA Huang J., Tu Z., Lee F.S.;
RT "Mutations in protein kinase subdomain X differentially affect MEKK2 and
RT MEKK1 activity.";
RL Biochem. Biophys. Res. Commun. 303:532-540(2003).
RN [4]
RP INTERACTION WITH MAP2K5.
RX PubMed=12912994; DOI=10.1074/jbc.c300313200;
RA Nakamura K., Johnson G.L.;
RT "PB1 domains of MEKK2 and MEKK3 interact with the MEK5 PB1 domain for
RT activation of the ERK5 pathway.";
RL J. Biol. Chem. 278:36989-36992(2003).
RN [5]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-331, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=17242355; DOI=10.1073/pnas.0609836104;
RA Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.;
RT "Large-scale phosphorylation analysis of mouse liver.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007).
RN [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-239; SER-331; SER-344 AND
RP SER-349, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Kidney, Lung, Pancreas, Spleen, and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
CC -!- FUNCTION: Component of a protein kinase signal transduction cascade.
CC Regulates the JNK and ERK5 pathways by phosphorylating and activating
CC MAP2K5 and MAP2K7. Plays a role in caveolae kiss-and-run dynamics (By
CC similarity). {ECO:0000250, ECO:0000269|PubMed:12659851}.
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=2.7.11.25;
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=2.7.11.25;
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC -!- ACTIVITY REGULATION: Activated by phosphorylation on Thr-524 (By
CC similarity). Interacts with PKN2; the interaction activates PKN2 kinase
CC activity in a MAP3K2-independent kinase activity. {ECO:0000250}.
CC -!- SUBUNIT: Self-associates (By similarity). Binds both upstream
CC activators and downstream substrates in multimolecular complexes.
CC Interacts (via the kinase catalytic domain) with STK38 (By similarity).
CC Interacts with XIAP/BIRC4 (By similarity). {ECO:0000250}.
CC -!- INTERACTION:
CC Q61083; Q9WVS7: Map2k5; NbExp=4; IntAct=EBI-446134, EBI-446144;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Upon EGF stimulation,
CC translocates into the nucleus.
CC -!- PTM: Ubiquitination by XIAP/BIRC4 does not lead to proteasomal
CC degradation. {ECO:0000250}.
CC -!- PTM: Autophosphorylated.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC protein kinase family. MAP kinase kinase kinase subfamily.
CC {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAB03536.1; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; U43186; AAB03536.1; ALT_FRAME; mRNA.
DR CCDS; CCDS29117.1; -.
DR AlphaFoldDB; Q61083; -.
DR SMR; Q61083; -.
DR IntAct; Q61083; 2.
DR MINT; Q61083; -.
DR STRING; 10090.ENSMUSP00000094326; -.
DR iPTMnet; Q61083; -.
DR PhosphoSitePlus; Q61083; -.
DR EPD; Q61083; -.
DR jPOST; Q61083; -.
DR MaxQB; Q61083; -.
DR PaxDb; Q61083; -.
DR PeptideAtlas; Q61083; -.
DR PRIDE; Q61083; -.
DR ProteomicsDB; 252699; -.
DR ABCD; Q61083; 4 sequenced antibodies.
DR MGI; MGI:1346873; Map3k2.
DR eggNOG; KOG0198; Eukaryota.
DR InParanoid; Q61083; -.
DR PhylomeDB; Q61083; -.
DR BRENDA; 2.7.12.2; 3474.
DR ChiTaRS; Map3k2; mouse.
DR PRO; PR:Q61083; -.
DR Proteomes; UP000000589; Unplaced.
DR RNAct; Q61083; protein.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; ISO:MGI.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004709; F:MAP kinase kinase kinase activity; ISO:MGI.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004672; F:protein kinase activity; ISO:MGI.
DR GO; GO:0019901; F:protein kinase binding; ISO:MGI.
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:0045893; P:positive regulation of transcription, DNA-templated; ISO:MGI.
DR GO; GO:0006468; P:protein phosphorylation; ISO:MGI.
DR CDD; cd06405; PB1_Mekk2_3; 1.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000270; PB1_dom.
DR InterPro; IPR034879; PB1_MEKK2/3.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR Pfam; PF00564; PB1; 1.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00666; PB1; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS51745; PB1; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
PE 1: Evidence at protein level;
KW ATP-binding; Cytoplasm; Kinase; Magnesium; Metal-binding;
KW Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; Transferase; Ubl conjugation.
FT CHAIN 1..619
FT /note="Mitogen-activated protein kinase kinase kinase 2"
FT /id="PRO_0000086244"
FT DOMAIN 43..122
FT /note="PB1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01081"
FT DOMAIN 356..616
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 25..44
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 126..168
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 201..247
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 289..355
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 126..140
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 201..221
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 289..319
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 334..351
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 483
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 362..370
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 385
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 26
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9Y2U5"
FT MOD_RES 153
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9Y2U5"
FT MOD_RES 164
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9Y2U5"
FT MOD_RES 239
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 297
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9Y2U5"
FT MOD_RES 311
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9Y2U5"
FT MOD_RES 331
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:17242355,
FT ECO:0007744|PubMed:21183079"
FT MOD_RES 344
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 349
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MUTAGEN 571
FT /note="F->A: No effect on autophosphorylation. Fails to
FT induce activation of the AP-1 transcription factor, MAPK7
FT or MAPK8."
FT /evidence="ECO:0000269|PubMed:12659851"
FT MUTAGEN 573
FT /note="I->A: Loss of autophosphorylation. Fails to induce
FT activation of the AP-1 transcription factor, MAPK7 or
FT MAPK8."
FT /evidence="ECO:0000269|PubMed:12659851"
FT MUTAGEN 575
FT /note="T->A: Loss of autophosphorylation and fails to
FT induce activation of the AP-1 transcription factor, MAPK7
FT or MAPK8; when associated with A-575 and A-576."
FT /evidence="ECO:0000269|PubMed:12659851"
FT MUTAGEN 576
FT /note="Q->A: Loss of autophosphorylation and fails to
FT induce activation of the AP-1 transcription factor, MAPK7
FT or MAPK8; when associated with A-574 and A-576."
FT /evidence="ECO:0000269|PubMed:12659851"
FT MUTAGEN 577
FT /note="P->A: Loss of autophosphorylation and fails to
FT induce activation of the AP-1 transcription factor, MAPK7
FT or MAPK8; when associated with A-575 and A-576."
FT /evidence="ECO:0000269|PubMed:12659851"
FT MUTAGEN 580
FT /note="P->A: Loss of autophosphorylation."
FT /evidence="ECO:0000269|PubMed:12659851"
FT MUTAGEN 582
FT /note="L->A: No effect on autophosphorylation and AP-1
FT transcription factor, MAPK7 or MAPK8 activity. Fails to
FT induce activation and loss of autophosphorylation; when
FT associated with A-582."
FT /evidence="ECO:0000269|PubMed:12659851"
FT MUTAGEN 583
FT /note="P->A: No effect on autophosphorylation and AP-1
FT transcription factor, MAPK7 or MAPK8 activity. Fails to
FT induce activation and loss of autophosphorylation; when
FT associated with A-581."
FT /evidence="ECO:0000269|PubMed:12659851"
FT MUTAGEN 586
FT /note="V->A: No effect on AP-1 transcription factor
FT activity."
FT /evidence="ECO:0000269|PubMed:12659851"
SQ SEQUENCE 619 AA; 69574 MW; 711DA492F18999B6 CRC64;
MDDQQALNSI MQDLAVLHKA SRPALSLQET RKAKPSSPKK QNDVRVKFEH RGEKRILQVT
RPVKLEDLRS KSKIAFGQSM DLHYTNNELV IPLTTQDDLD KAVELLDRSI HMKSLKILLV
VNGSTQATNL EPSPSPEDLN NTPLGAERKK RLSVVGPPNR DRSSPPPGYI PDILHQIARN
GSFTSINSEG EFIPESMDQM LDPLSLSSPE NSGSGSCPSL DSPLDGESYP KSRMPRAQSY
PDNHQEFTDY DNPIFEKFGK GGTYPRRYHV SYHHQEYNDG RKTFPRARRT QGTSFRSPVS
FSPTDHSLST SSGSSVFTPE YDDSRIRRRG SDIDNPTLTV TDISPPSRSP RAPTNWRLGK
LLGQGAFGRV YLCYDVDTGR ELAVKQVQFN PESPETSKEV NALECEIQLL KNLLHERIVQ
YYGCLRDPQE KTLSIFMELS PGGSIKDQLK AYGALTENVT RKYTRQILEG VHYLHSNMIV
HRDIKGANIL RDSTGNIKLG DFGASKRLQT ICLSGTGMKS VTGTPYWMSP EVISGEGYGR
KADIWSVACT VVEMLTEKPP WAEFEAMAAI FKIATQPTNP KLPPHVSDYT RDFLKRIFVE
AKLRPSAEEL LRHMFVHYH
