MLK1_CAEEL
ID MLK1_CAEEL Reviewed; 1059 AA.
AC A0A0K3AV08; A0A0K3AS83; H2KYR3; Q8T7Z0;
DT 16-MAR-2016, integrated into UniProtKB/Swiss-Prot.
DT 11-NOV-2015, sequence version 1.
DT 03-AUG-2022, entry version 47.
DE RecName: Full=Mitogen-activated protein kinase kinase kinase mlk-1 {ECO:0000305};
DE EC=2.7.11.25 {ECO:0000269|PubMed:15116070, ECO:0000269|PubMed:20008556};
DE AltName: Full=Mixed lineage kinase homolog 1 {ECO:0000312|EMBL:CTQ86850.1};
GN Name=mlk-1 {ECO:0000312|EMBL:CTQ86850.1};
GN ORFNames=K11D12.10 {ECO:0000312|EMBL:CTQ86850.1};
OS Caenorhabditis elegans.
OC Eukaryota; Metazoa; Ecdysozoa; Nematoda; Chromadorea; Rhabditida;
OC Rhabditina; Rhabditomorpha; Rhabditoidea; Rhabditidae; Peloderinae;
OC Caenorhabditis.
OX NCBI_TaxID=6239 {ECO:0000312|Proteomes:UP000001940};
RN [1] {ECO:0000312|Proteomes:UP000001940}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Bristol N2 {ECO:0000312|EMBL:CTQ86850.1,
RC ECO:0000312|Proteomes:UP000001940};
RX PubMed=9851916; DOI=10.1126/science.282.5396.2012;
RG The C. elegans sequencing consortium;
RT "Genome sequence of the nematode C. elegans: a platform for investigating
RT biology.";
RL Science 282:2012-2018(1998).
RN [2] {ECO:0000305}
RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF GLY-253.
RX PubMed=15116070; DOI=10.1038/sj.emboj.7600226;
RA Mizuno T., Hisamoto N., Terada T., Kondo T., Adachi M., Nishida E.,
RA Kim D.H., Ausubel F.M., Matsumoto K.;
RT "The Caenorhabditis elegans MAPK phosphatase VHP-1 mediates a novel JNK-
RT like signaling pathway in stress response.";
RL EMBO J. 23:2226-2234(2004).
RN [3] {ECO:0000305}
RP FUNCTION, INTERACTION WITH SHC-1, TISSUE SPECIFICITY, MOTIF,
RP PHOSPHORYLATION AT TYR-940, AND MUTAGENESIS OF TYR-940.
RX PubMed=18809575; DOI=10.1128/mcb.00938-08;
RA Mizuno T., Fujiki K., Sasakawa A., Hisamoto N., Matsumoto K.;
RT "Role of the Caenorhabditis elegans Shc adaptor protein in the c-Jun N-
RT terminal kinase signaling pathway.";
RL Mol. Cell. Biol. 28:7041-7049(2008).
RN [4] {ECO:0000305}
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, INTERACTION WITH MAX-2,
RP PHOSPHORYLATION AT SER-355, AND MUTAGENESIS OF LYS-193 AND SER-355.
RX PubMed=20008556; DOI=10.1128/mcb.01131-09;
RA Fujiki K., Mizuno T., Hisamoto N., Matsumoto K.;
RT "The Caenorhabditis elegans Ste20-related kinase and Rac-type small GTPase
RT regulate the c-Jun N-terminal kinase signaling pathway mediating the stress
RT response.";
RL Mol. Cell. Biol. 30:995-1003(2010).
RN [5] {ECO:0000305}
RP FUNCTION, AND UBIQUITINATION.
RX PubMed=21670305; DOI=10.1073/pnas.1104830108;
RA Nix P., Hisamoto N., Matsumoto K., Bastiani M.;
RT "Axon regeneration requires coordinate activation of p38 and JNK MAPK
RT pathways.";
RL Proc. Natl. Acad. Sci. U.S.A. 108:10738-10743(2011).
RN [6] {ECO:0000305}
RP FUNCTION, ACTIVITY REGULATION, INTERACTION WITH TPA-1, PHOSPHORYLATION AT
RP SER-355, AND MUTAGENESIS OF SER-355.
RX PubMed=23072806; DOI=10.1038/ncomms2136;
RA Pastuhov S.I., Fujiki K., Nix P., Kanao S., Bastiani M., Matsumoto K.,
RA Hisamoto N.;
RT "Endocannabinoid-Goalpha signalling inhibits axon regeneration in
RT Caenorhabditis elegans by antagonizing Gqalpha-PKC-JNK signalling.";
RL Nat. Commun. 3:1136-1136(2012).
RN [7] {ECO:0000305}
RP FUNCTION, ACTIVITY REGULATION, INTERACTION WITH SVH-2, AND PHOSPHORYLATION.
RX PubMed=22388962; DOI=10.1038/nn.3052;
RA Li C., Hisamoto N., Nix P., Kanao S., Mizuno T., Bastiani M., Matsumoto K.;
RT "The growth factor SVH-1 regulates axon regeneration in C. elegans via the
RT JNK MAPK cascade.";
RL Nat. Neurosci. 15:551-557(2012).
RN [8]
RP PHOSPHORYLATION.
RX PubMed=27984580; DOI=10.1371/journal.pgen.1006475;
RA Hisamoto N., Nagamori Y., Shimizu T., Pastuhov S.I., Matsumoto K.;
RT "The C. elegans discoidin domain receptor DDR-2 modulates the Met-like RTK-
RT JNK signaling pathway in axon regeneration.";
RL PLoS Genet. 12:E1006475-E1006475(2016).
CC -!- FUNCTION: Serine/threonine-protein kinase which, by phosphorylating and
CC activating mek-1, plays an important role in the activation of the JNK
CC pathway composed of mlk-1, mek-1 and kgb-1 (PubMed:15116070,
CC PubMed:20008556). Involved in the response to environmental stress such
CC as heavy metals (PubMed:15116070, PubMed:18809575). By activating the
CC JNK pathway downstream of tyrosine receptor svh-2, plays a role in axon
CC regeneration after injury (PubMed:21670305, PubMed:23072806,
CC PubMed:22388962). {ECO:0000269|PubMed:15116070,
CC ECO:0000269|PubMed:18809575, ECO:0000269|PubMed:20008556,
CC ECO:0000269|PubMed:21670305, ECO:0000269|PubMed:22388962,
CC ECO:0000269|PubMed:23072806}.
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 Evidence={ECO:0000269|PubMed:15116070, ECO:0000269|PubMed:20008556};
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; Evidence={ECO:0000269|PubMed:15116070,
CC ECO:0000269|PubMed:20008556};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:P80192};
CC -!- ACTIVITY REGULATION: Activated by phosphorylation at Ser-355
CC (PubMed:20008556). May be activated by svh-2-mediated phosphorylation
CC (PubMed:23072806, PubMed:22388962). {ECO:0000269|PubMed:20008556,
CC ECO:0000269|PubMed:22388962, ECO:0000269|PubMed:23072806}.
CC -!- SUBUNIT: Interacts with max-2; the interaction is independent of max-2
CC and mlk-1 kinase activities (PubMed:20008556). May interact (via NPQY
CC motif when phosphorylated on tyrosine residue) with shc-1 (via PID
CC domain); the interaction may facilitate mek-1 phosphorylation by
CC bringing mlk-1 and mek-1 together (PubMed:18809575). Interacts with
CC svh-2 (via cytoplasmic domain) (PubMed:22388962). Interacts with tpa-1
CC (PubMed:23072806). {ECO:0000269|PubMed:18809575,
CC ECO:0000269|PubMed:20008556, ECO:0000269|PubMed:22388962,
CC ECO:0000269|PubMed:23072806}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=c {ECO:0000312|WormBase:K11D12.10c};
CC IsoId=A0A0K3AV08-1; Sequence=Displayed;
CC Name=a {ECO:0000312|WormBase:K11D12.10a};
CC IsoId=A0A0K3AV08-2; Sequence=VSP_058148;
CC Name=b {ECO:0000312|WormBase:K11D12.10b};
CC IsoId=A0A0K3AV08-3; Sequence=VSP_058147;
CC Name=d {ECO:0000312|WormBase:K11D12.10d};
CC IsoId=A0A0K3AV08-4; Sequence=VSP_058147, VSP_058148;
CC -!- TISSUE SPECIFICITY: Expressed in pharynx, intestine, hypodermis,
CC neurons and body muscles. {ECO:0000269|PubMed:18809575}.
CC -!- PTM: May be phosphorylated on tyrosine residues by svh-2.
CC {ECO:0000269|PubMed:22388962, ECO:0000269|PubMed:27984580}.
CC -!- PTM: May be ubiquitinated and targeted for proteosomal degradation by
CC E3 ubiquitin ligase rpm-1. {ECO:0000269|PubMed:21670305}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC protein kinase family. MAP kinase kinase kinase subfamily.
CC {ECO:0000305}.
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DR EMBL; BX284605; CCD64404.1; -; Genomic_DNA.
DR EMBL; BX284605; CCD64405.1; -; Genomic_DNA.
DR EMBL; BX284605; CTQ86850.1; -; Genomic_DNA.
DR EMBL; BX284605; CTQ86851.1; -; Genomic_DNA.
DR RefSeq; NP_001300151.1; NM_001313222.1. [A0A0K3AV08-1]
DR RefSeq; NP_001300152.1; NM_001313223.1. [A0A0K3AV08-4]
DR RefSeq; NP_741536.1; NM_171456.5. [A0A0K3AV08-3]
DR RefSeq; NP_741537.1; NM_171928.3. [A0A0K3AV08-2]
DR AlphaFoldDB; A0A0K3AV08; -.
DR SMR; A0A0K3AV08; -.
DR DIP; DIP-25180N; -.
DR IntAct; A0A0K3AV08; 4.
DR STRING; 6239.K11D12.10a; -.
DR iPTMnet; A0A0K3AV08; -.
DR PaxDb; A0A0K3AV08; -.
DR EnsemblMetazoa; K11D12.10a.1; K11D12.10a.1; WBGene00003374. [A0A0K3AV08-2]
DR EnsemblMetazoa; K11D12.10b.1; K11D12.10b.1; WBGene00003374. [A0A0K3AV08-3]
DR EnsemblMetazoa; K11D12.10c.1; K11D12.10c.1; WBGene00003374. [A0A0K3AV08-1]
DR EnsemblMetazoa; K11D12.10d.1; K11D12.10d.1; WBGene00003374. [A0A0K3AV08-4]
DR GeneID; 178895; -.
DR KEGG; cel:CELE_K11D12.10; -.
DR UCSC; K11D12.10b; c. elegans.
DR CTD; 178895; -.
DR WormBase; K11D12.10a; CE30383; WBGene00003374; mlk-1. [A0A0K3AV08-2]
DR WormBase; K11D12.10b; CE30384; WBGene00003374; mlk-1. [A0A0K3AV08-3]
DR WormBase; K11D12.10c; CE50686; WBGene00003374; mlk-1. [A0A0K3AV08-1]
DR WormBase; K11D12.10d; CE50749; WBGene00003374; mlk-1. [A0A0K3AV08-4]
DR eggNOG; KOG0192; Eukaryota.
DR GeneTree; ENSGT00940000163262; -.
DR OMA; YAWLAPE; -.
DR OrthoDB; 420567at2759; -.
DR SignaLink; A0A0K3AV08; -.
DR PRO; PR:A0A0K3AV08; -.
DR Proteomes; UP000001940; Chromosome V.
DR Bgee; WBGene00003374; Expressed in pharyngeal muscle cell (C elegans) and 3 other tissues.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004709; F:MAP kinase kinase kinase activity; IEA:UniProtKB-EC.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004672; F:protein kinase activity; IBA:GO_Central.
DR GO; GO:0019901; F:protein kinase binding; IPI:WormBase.
DR GO; GO:0005080; F:protein kinase C binding; IPI:UniProtKB.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0030971; F:receptor tyrosine kinase binding; IPI:UniProtKB.
DR GO; GO:0097110; F:scaffold protein binding; IPI:UniProtKB.
DR GO; GO:0031103; P:axon regeneration; IGI:UniProtKB.
DR GO; GO:0050829; P:defense response to Gram-negative bacterium; IMP:UniProtKB.
DR GO; GO:0008340; P:determination of adult lifespan; IMP:UniProtKB.
DR GO; GO:0007254; P:JNK cascade; IMP:UniProtKB.
DR GO; GO:0000165; P:MAPK cascade; IMP:UniProtKB.
DR GO; GO:0038066; P:p38MAPK cascade; IMP:WormBase.
DR GO; GO:0048691; P:positive regulation of axon extension involved in regeneration; IMP:UniProtKB.
DR GO; GO:0048680; P:positive regulation of axon regeneration; IMP:UniProtKB.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IMP:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; IMP:WormBase.
DR GO; GO:0046688; P:response to copper ion; IMP:WormBase.
DR GO; GO:0042594; P:response to starvation; IMP:UniProtKB.
DR GO; GO:0007165; P:signal transduction; IBA:GO_Central.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR InterPro; IPR036028; SH3-like_dom_sf.
DR InterPro; IPR001452; SH3_domain.
DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1.
DR Pfam; PF14604; SH3_9; 1.
DR SMART; SM00220; S_TKc; 1.
DR SMART; SM00326; SH3; 1.
DR SUPFAM; SSF50044; SSF50044; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
DR PROSITE; PS50002; SH3; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; ATP-binding; Coiled coil; Kinase; Magnesium;
KW Metal-binding; Nucleotide-binding; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; SH3 domain; Stress response; Transferase;
KW Ubl conjugation.
FT CHAIN 1..1059
FT /note="Mitogen-activated protein kinase kinase kinase mlk-
FT 1"
FT /evidence="ECO:0000305"
FT /id="PRO_0000435680"
FT DOMAIN 69..130
FT /note="SH3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00192"
FT DOMAIN 150..454
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 1..66
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 617..699
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 714..808
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COILED 199..224
FT /evidence="ECO:0000255"
FT MOTIF 937..940
FT /note="NPQY motif"
FT /evidence="ECO:0000269|PubMed:18809575"
FT COMPBIAS 37..66
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 620..636
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 637..651
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 660..676
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 677..699
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 724..759
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 770..808
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 297
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 156..164
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 193
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 355
FT /note="Phosphoserine; by max-2 and tpa-1"
FT /evidence="ECO:0000269|PubMed:20008556,
FT ECO:0000269|PubMed:23072806"
FT MOD_RES 940
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000269|PubMed:18809575"
FT VAR_SEQ 551..631
FT /note="Missing (in isoform b and isoform d)"
FT /evidence="ECO:0000305"
FT /id="VSP_058147"
FT VAR_SEQ 726..748
FT /note="NTTKKHKVSPSDKRPVKTTNQTE -> NTTK (in isoform a and
FT isoform d)"
FT /evidence="ECO:0000305"
FT /id="VSP_058148"
FT MUTAGEN 193
FT /note="K->R: Loss of kinase activity. No effect on the
FT interaction with max-2. No effect on phosphorylation of
FT Ser-355 by max-2."
FT /evidence="ECO:0000269|PubMed:20008556"
FT MUTAGEN 253
FT /note="G->R: In km701; rescues growth arrest at larval L2-
FT L3 stages in vhp-1 km20 mutant."
FT /evidence="ECO:0000269|PubMed:15116070"
FT MUTAGEN 355
FT /note="S->A: Abolishes phosphorylation by max-2. Loss of
FT kinase activity. No effect on the interaction with max-2.
FT Loss of resistance to heavy metal ions such as Cu(2+).
FT Impaired axon regeneration after injury."
FT /evidence="ECO:0000269|PubMed:20008556,
FT ECO:0000269|PubMed:23072806"
FT MUTAGEN 355
FT /note="S->E,D: Phosphomimetic mutant which probably causes
FT constitutive kinase activation and results in mek-1
FT phosphorylation. Resistance to arachidonoyl ethanolamide
FT (AEA)-mediated inhibition of axon regeneration after
FT injury."
FT /evidence="ECO:0000269|PubMed:20008556,
FT ECO:0000269|PubMed:23072806"
FT MUTAGEN 940
FT /note="Y->F: May abolish interaction with shc-2. Severe
FT loss of resistance to heavy metal ions such as Cu(2+)."
FT /evidence="ECO:0000269|PubMed:18809575"
SQ SEQUENCE 1059 AA; 117635 MW; 1906D103040CCFBE CRC64;
MEQASVPSYV NIPPIAKTRS TSHLAPTPEH HRSVSYEDTT TASTSTDSVP EVRIRSESSQ
VSRESPPIRA SKAFVASYEY EAQKDDELNL PLGAIITLVT VETNEDGWYR GELNGKVGLF
PSNYAREVTY KDNLVEFKQD EIMLPVAVRT LSDCQIGHGA TATVFKMDIK IKKELQNGRM
GEAVGDQMKA ALKRFNRHAS NFRADVVSTD EQLEQLKREA NLVNGLSHNN IVRLLGICLE
DPYFGLLLEL CEGSSLRNVC RNLNSDAAIP LGVLIDWATQ VAEGMEYLTK QGYVHRDLKA
DNVLVKEEVC LCMDEEMFQY AYCLKCGKRP FDKLQLKITD FGVTRKMTAD ANRFSTAGTY
AWLAPEAFKE GTWSEASDVW SYGVVLWELL TREEPYQGHI PATIAFQIAN KGQNLSIGDS
CPDRWKKLMQ DCWNLEPNFR PKFSTLAISF KQYAKEFKDT HLQRAPSKMA VKELYSECFA
DKTKEEFEKR FHDLYAGSGD INRKNRHSIA PETKARRLKH HKPKKADITG PTEVKHILSV
QKDDKNFRVK TYDQSSTGGT LPRLNERQST LSLSSPDLFH ISNLISGSNT VGHSAHRISR
KNAIRHKKNQ HRMFESPVVS PTMDDSNTFS TIDNADEVDP NHSKESKKGG TLSRAWAKLP
WNKRDSKEDH DERAVAGSIS SRSSSTTSSN RLITGQTTRG ASAAGLLEIG ARSRAQSTAD
GWEDPNTTKK HKVSPSDKRP VKTTNQTERY VKDLEKDTPL RPAQLPPTHR KSALDQTIPA
SPNSPDSINN FHPMPLSSRR TTANSSSDGA PCYDALVSHS YGAGHGHKNH FGLSDTIPLF
PEEPTHYDMG PGRPFGTNGR AIVNQGGDYY GNISGQNYEG FGHGRSINQS TQYYPVGGGC
DDYIPIVQKT VIKPTVGEVG NSPYSENIRC ATRNVQNPQY IQCKKNQNPR RIPALPMKIQ
SESNLVTSGM VFTPRDEQLN GIGNSLSSLS LNEPPDIPAP LPPVVTYPIP ASLISPSNRV
SMSPPTRMAP VLPLGAMSSP RIMDKEILKN SSVEGTEIY
