MELK_CAEEL
ID MELK_CAEEL Reviewed; 706 AA.
AC U4PR86; A7WK47; A7WK48; U4PB44; U4PBH9; U4PED2; U4PLZ7; U4PR90;
DT 04-MAR-2015, integrated into UniProtKB/Swiss-Prot.
DT 11-DEC-2013, sequence version 1.
DT 03-AUG-2022, entry version 61.
DE RecName: Full=Maternal embryonic leucine zipper kinase {ECO:0000250|UniProtKB:Q14680};
DE Short=MELK {ECO:0000250|UniProtKB:Q14680};
DE EC=2.7.11.1 {ECO:0000250|UniProtKB:Q14680};
GN Name=pig-1 {ECO:0000312|WormBase:W03G1.6c};
GN ORFNames=W03G1.6 {ECO:0000312|WormBase:W03G1.6c};
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|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, SUBCELLULAR LOCATION, DEVELOPMENTAL STAGE, DISRUPTION PHENOTYPE,
RP AND MUTAGENESIS OF GLY-172 AND GLY-198.
RX PubMed=16774992; DOI=10.1242/dev.02447;
RA Cordes S., Frank C.A., Garriga G.;
RT "The C. elegans MELK ortholog PIG-1 regulates cell size asymmetry and
RT daughter cell fate in asymmetric neuroblast divisions.";
RL Development 133:2747-2756(2006).
RN [3] {ECO:0000305}
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=20929735; DOI=10.1126/science.1196112;
RA Ou G., Stuurman N., D'Ambrosio M., Vale R.D.;
RT "Polarized myosin produces unequal-size daughters during asymmetric cell
RT division.";
RL Science 330:677-680(2010).
RN [4] {ECO:0000305}
RP FUNCTION, DISRUPTION PHENOTYPE, AND MUTAGENESIS OF THR-169.
RX PubMed=22801495; DOI=10.1038/nature11240;
RA Denning D.P., Hatch V., Horvitz H.R.;
RT "Programmed elimination of cells by caspase-independent cell extrusion in
RT C. elegans.";
RL Nature 488:226-230(2012).
RN [5] {ECO:0000305}
RP FUNCTION.
RX PubMed=23946438; DOI=10.1242/dev.098723;
RA Feng G., Yi P., Yang Y., Chai Y., Tian D., Zhu Z., Liu J., Zhou F.,
RA Cheng Z., Wang X., Li W., Ou G.;
RT "Developmental stage-dependent transcriptional regulatory pathways control
RT neuroblast lineage progression.";
RL Development 140:3838-3847(2013).
RN [6] {ECO:0000305}
RP FUNCTION, SUBCELLULAR LOCATION, DOMAIN, AND MUTAGENESIS OF THR-169 AND
RP GLY-198.
RX PubMed=23267054; DOI=10.1534/genetics.112.148106;
RA Chien S.C., Brinkmann E.M., Teuliere J., Garriga G.;
RT "Caenorhabditis elegans PIG-1/MELK acts in a conserved PAR-4/LKB1 polarity
RT pathway to promote asymmetric neuroblast divisions.";
RL Genetics 193:897-909(2013).
RN [7] {ECO:0000305}
RP FUNCTION, AND MUTAGENESIS OF GLY-172.
RX PubMed=23851392; DOI=10.1038/nature12329;
RA Hirose T., Horvitz H.R.;
RT "An Sp1 transcription factor coordinates caspase-dependent and -independent
RT apoptotic pathways.";
RL Nature 500:354-358(2013).
RN [8]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=28659600; DOI=10.1038/s41598-017-04375-4;
RA Offenburger S.L., Bensaddek D., Murillo A.B., Lamond A.I., Gartner A.;
RT "Comparative genetic, proteomic and phosphoproteomic analysis of C. elegans
RT embryos with a focus on ham-1/STOX and pig-1/MELK in dopaminergic neuron
RT development.";
RL Sci. Rep. 7:4314-4314(2017).
CC -!- FUNCTION: Serine/threonine-protein kinase involved in cell autonomous
CC neuroblast asymmetric divisions that generate one precursor cell and
CC one apoptotic cell by controlling spindle positioning, myosin
CC distribution and the segregation of cell fate determinants
CC (PubMed:16774992, PubMed:20929735, PubMed:23946438, PubMed:23267054,
CC PubMed:23851392, PubMed:28659600). Plays a role in neural fate
CC specification in several dopaminergic linages, acting in concert with
CC ham-1 (PubMed:28659600). Involved in phosphorylation of multiple
CC proteins associated with key developmental processes, including the
CC cell cycle, apoptosis, endocytosis, and asymmetric cell division
CC (PubMed:28659600). Promotes cell shedding during embryogenesis,
CC probably through the endocytosis-mediated removal of cell adhesion
CC molecules such as hmp-1 from the cell surface (PubMed:22801495). May
CC act downstream of par-4/strd-1/mop-25 to regulate cell shedding
CC (PubMed:22801495). {ECO:0000269|PubMed:16774992,
CC ECO:0000269|PubMed:20929735, ECO:0000269|PubMed:22801495,
CC ECO:0000269|PubMed:23267054, ECO:0000269|PubMed:23851392,
CC ECO:0000269|PubMed:23946438, ECO:0000269|PubMed:28659600}.
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 Evidence={ECO:0000250|UniProtKB:Q14680};
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; Evidence={ECO:0000250|UniProtKB:Q14680};
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16774992}.
CC Cytoplasm, cytoskeleton, microtubule organizing center, centrosome
CC {ECO:0000269|PubMed:23267054}. Note=Cytoplasmic in undividing cells and
CC co-localizes with centrosome in dividing cells.
CC {ECO:0000269|PubMed:23267054}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=8;
CC Name=c {ECO:0000312|WormBase:W03G1.6c};
CC IsoId=U4PR86-1; Sequence=Displayed;
CC Name=a {ECO:0000312|WormBase:W03G1.6a};
CC IsoId=U4PR86-2; Sequence=VSP_057507;
CC Name=b {ECO:0000312|WormBase:W03G1.6b};
CC IsoId=U4PR86-3; Sequence=VSP_057507, VSP_057508;
CC Name=d {ECO:0000312|WormBase:W03G1.6d};
CC IsoId=U4PR86-4; Sequence=VSP_057508;
CC Name=e {ECO:0000312|WormBase:W03G1.6e};
CC IsoId=U4PR86-5; Sequence=VSP_057506, VSP_057507;
CC Name=f {ECO:0000312|WormBase:W03G1.6f};
CC IsoId=U4PR86-6; Sequence=VSP_057506, VSP_057507, VSP_057508;
CC Name=g {ECO:0000312|WormBase:W03G1.6g};
CC IsoId=U4PR86-7; Sequence=VSP_057506;
CC Name=h {ECO:0000312|WormBase:W03G1.6h};
CC IsoId=U4PR86-8; Sequence=VSP_057506, VSP_057508;
CC -!- DEVELOPMENTAL STAGE: Ubiquitously expressed in early embryo with a more
CC restricted expression in later embryonic stages and in young larvae.
CC Expressed in dividing cells including ventral nerve cord neuroblasts,
CC vulval precursors, hypodermal seam cells and in the Q lineage. No
CC expression in adults. {ECO:0000269|PubMed:16774992}.
CC -!- DOMAIN: The KA1 domain is required for the control of asymmetric
CC neuroblast division. {ECO:0000269|PubMed:23267054}.
CC -!- PTM: May be phosphorylated at Thr-169 by par-4 and/or
CC autophosphorylated which likely results in its activation
CC (PubMed:22801495). Phosphorylation is not required for co-localization
CC with the centrosome (PubMed:23267054). {ECO:0000269|PubMed:22801495,
CC ECO:0000269|PubMed:23267054}.
CC -!- DISRUPTION PHENOTYPE: During neuroblast differentiation, mutants
CC produce an additional precursor cell for the HSN/PHB, I2, M4 and
CC PLM/ALN and Q.a and Q.p lineages. The nucleus size of the 2 Q.p
CC daughter cells is similar (PubMed:16774992). Symmetrical distribution
CC of myosin II during QR.a cell division (PubMed:20929735). Abnormally
CC high number of ADE neurons (PubMed:28659600). Double knockouts of pig-1
CC and ced-3 have impaired cell shedding during embryogenesis which
CC results in the generation of an ectopic excretory cell and an ERM-like
CC neuron. In addition, mutants show a delay in clearance after engulfment
CC of cell corpses which is associated with the abnormal expression of
CC cell adhesion molecules (PubMed:22801495).
CC {ECO:0000269|PubMed:16774992, ECO:0000269|PubMed:20929735,
CC ECO:0000269|PubMed:22801495, ECO:0000269|PubMed:28659600}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CAMK Ser/Thr
CC protein kinase family. SNF1 subfamily. {ECO:0000305}.
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DR EMBL; FO081096; CCD69087.1; -; Genomic_DNA.
DR EMBL; FO081096; CCD69088.1; -; Genomic_DNA.
DR EMBL; FO081096; CDH93078.1; -; Genomic_DNA.
DR EMBL; FO081096; CDH93079.1; -; Genomic_DNA.
DR EMBL; FO081096; CDH93080.1; -; Genomic_DNA.
DR EMBL; FO081096; CDH93081.1; -; Genomic_DNA.
DR EMBL; FO081096; CDH93082.1; -; Genomic_DNA.
DR EMBL; FO081096; CDH93083.1; -; Genomic_DNA.
DR RefSeq; NP_001023420.2; NM_001028249.3. [U4PR86-2]
DR RefSeq; NP_001023421.2; NM_001028250.2. [U4PR86-3]
DR RefSeq; NP_001294353.1; NM_001307424.1. [U4PR86-1]
DR RefSeq; NP_001294354.1; NM_001307425.1. [U4PR86-4]
DR RefSeq; NP_001294355.1; NM_001307426.1.
DR RefSeq; NP_001294356.1; NM_001307427.1.
DR RefSeq; NP_001294357.1; NM_001307428.1. [U4PR86-7]
DR RefSeq; NP_001294358.1; NM_001307429.1. [U4PR86-8]
DR AlphaFoldDB; U4PR86; -.
DR SMR; U4PR86; -.
DR IntAct; U4PR86; 1.
DR STRING; 6239.W03G1.6c; -.
DR EPD; U4PR86; -.
DR PaxDb; U4PR86; -.
DR PeptideAtlas; U4PR86; -.
DR EnsemblMetazoa; W03G1.6a.1; W03G1.6a.1; WBGene00021012. [U4PR86-2]
DR EnsemblMetazoa; W03G1.6b.1; W03G1.6b.1; WBGene00021012. [U4PR86-3]
DR EnsemblMetazoa; W03G1.6c.1; W03G1.6c.1; WBGene00021012. [U4PR86-1]
DR EnsemblMetazoa; W03G1.6d.1; W03G1.6d.1; WBGene00021012. [U4PR86-4]
DR EnsemblMetazoa; W03G1.6e.1; W03G1.6e.1; WBGene00021012. [U4PR86-5]
DR EnsemblMetazoa; W03G1.6f.1; W03G1.6f.1; WBGene00021012. [U4PR86-6]
DR EnsemblMetazoa; W03G1.6g.1; W03G1.6g.1; WBGene00021012. [U4PR86-7]
DR EnsemblMetazoa; W03G1.6h.1; W03G1.6h.1; WBGene00021012. [U4PR86-8]
DR GeneID; 176877; -.
DR KEGG; cel:CELE_W03G1.6; -.
DR UCSC; W03G1.6a; c. elegans.
DR CTD; 176877; -.
DR WormBase; W03G1.6a; CE40473; WBGene00021012; pig-1. [U4PR86-2]
DR WormBase; W03G1.6b; CE40474; WBGene00021012; pig-1. [U4PR86-3]
DR WormBase; W03G1.6c; CE48676; WBGene00021012; pig-1. [U4PR86-1]
DR WormBase; W03G1.6d; CE49097; WBGene00021012; pig-1. [U4PR86-4]
DR WormBase; W03G1.6e; CE48957; WBGene00021012; pig-1. [U4PR86-5]
DR WormBase; W03G1.6f; CE48801; WBGene00021012; pig-1. [U4PR86-6]
DR WormBase; W03G1.6g; CE48617; WBGene00021012; pig-1. [U4PR86-7]
DR WormBase; W03G1.6h; CE49061; WBGene00021012; pig-1. [U4PR86-8]
DR eggNOG; KOG0583; Eukaryota.
DR GeneTree; ENSGT00940000154889; -.
DR OMA; LRAHYNV; -.
DR OrthoDB; 1127668at2759; -.
DR PRO; PR:U4PR86; -.
DR Proteomes; UP000001940; Chromosome IV.
DR Bgee; WBGene00021012; Expressed in embryo and 4 other tissues.
DR GO; GO:0005813; C:centrosome; IDA:WormBase.
DR GO; GO:0005737; C:cytoplasm; IDA:WormBase.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004715; F:non-membrane spanning protein tyrosine kinase activity; IBA:GO_Central.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IMP:UniProtKB.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0055059; P:asymmetric neuroblast division; IMP:UniProtKB.
DR GO; GO:0071542; P:dopaminergic neuron differentiation; IGI:UniProtKB.
DR GO; GO:0031581; P:hemidesmosome assembly; IGI:WormBase.
DR GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central.
DR GO; GO:1904746; P:negative regulation of apoptotic process involved in development; IGI:UniProtKB.
DR GO; GO:0014019; P:neuroblast development; IMP:UniProtKB.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IMP:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; IMP:UniProtKB.
DR GO; GO:0030155; P:regulation of cell adhesion; IGI:UniProtKB.
DR CDD; cd14078; STKc_MELK; 1.
DR InterPro; IPR028375; KA1/Ssp2_C.
DR InterPro; IPR001772; KA1_dom.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR034673; MELK.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF02149; KA1; 1.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF103243; SSF103243; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS50032; KA1; 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 Alternative splicing; Apoptosis; ATP-binding; Cytoplasm; Cytoskeleton;
KW Developmental protein; Kinase; Neurogenesis; Nucleotide-binding;
KW Reference proteome; Serine/threonine-protein kinase; Transferase.
FT CHAIN 1..706
FT /note="Maternal embryonic leucine zipper kinase"
FT /id="PRO_0000432387"
FT DOMAIN 11..265
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT DOMAIN 656..705
FT /note="KA1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00565"
FT REGION 366..386
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 433..493
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 506..555
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 433..460
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 132
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 17..25
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 40
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT VAR_SEQ 1..244
FT /note="Missing (in isoform e, isoform f, isoform g and
FT isoform h)"
FT /evidence="ECO:0000305"
FT /id="VSP_057506"
FT VAR_SEQ 561..563
FT /note="Missing (in isoform a, isoform b, isoform e and
FT isoform f)"
FT /evidence="ECO:0000305"
FT /id="VSP_057507"
FT VAR_SEQ 679..706
FT /note="GIRRKRLKGDAFMYKKVCEKILQMAKIE -> RNLRRFFCCVNINIPSRKPT
FT YIEL (in isoform b, isoform d, isoform f and isoform h)"
FT /evidence="ECO:0000305"
FT /id="VSP_057508"
FT MUTAGEN 169
FT /note="T->A: May be inactive. Prevents cell shedding during
FT embryogenesis. Additional production of PVM neuron."
FT /evidence="ECO:0000269|PubMed:22801495,
FT ECO:0000269|PubMed:23267054"
FT MUTAGEN 169
FT /note="T->D: May be constitutively active. Promotes cell
FT shedding during embryogenesis. In some mutants, production
FT of an additional PVM neuron."
FT /evidence="ECO:0000269|PubMed:22801495,
FT ECO:0000269|PubMed:23267054"
FT MUTAGEN 172
FT /note="G->E: In n4780; production of an additional M4 motor
FT neuron."
FT /evidence="ECO:0000269|PubMed:23851392"
FT MUTAGEN 172
FT /note="G->R: In gm300; production of an additional HSN/PHB
FT precursor cell."
FT /evidence="ECO:0000269|PubMed:16774992"
FT MUTAGEN 198
FT /note="G->D: In gm301; production of an additional HSN/PHB
FT precursor cell and an additional PVM precursor cell."
FT /evidence="ECO:0000269|PubMed:16774992,
FT ECO:0000269|PubMed:23267054"
SQ SEQUENCE 706 AA; 80340 MW; 7A6A330E2F5C4E2A CRC64;
MSKYEVLQGF YAVHDELGSG GFGKVRLATH LLTNQKVAIK IIDKKQLGHD LPRVQTEMDA
LRNLSHQNIC RLYHYIETED KFFIVMEYCS GGEMFDYIVR KERLEESEAR HFFRQLVSAI
AFVHSQGYAH RDLKPENLLL TEDLHLKLID FGLCAKTEKG RIDKHNLDTC CGSPAYAAPE
LIQGLQYKGN EADVWSMGIL LYTLLVGALP FEDDNMQIMY KKIQSGCFYE PEFLSPLSKQ
LLRAMLQVVP ERRISVKKLL EHDWLNHKYT QPVKWNTIYD KNFIDRDVAR VMSKYYGFES
TDKMIEKIKE WNFDYMTSTY YALLHRKRNG MEIILPMVRN STNTAPPNVQ NILCSPTIHA
SLENNLDKSG LEDDDSDPSS ISSSSDISAR LKKNCVVSDE SSSSRFVKPM SPAAEKDKKM
SYVNAMLTMP SQFTGRSPLR IPESPMSVRS SDSASLGSAA TPSRGGVKDN DKENASTGKN
YRMGASTCKS RGPLKITGVE EGTMKSVYTT PNTRPTLRGL FSPGNAEHKK RQRARSSDRA
SIGMPPGSPV SIGSAHSANN ELLADGRTPR SRIKTNRLPQ RVFTSLERKK EKLITLLTPR
KMQRDSPQVL KDVKNMVNVS MTASQDPEEV RNLLKKVFDD ERMRYELNGW KFLATQETVH
GWMTVELEIV RLQMFDKVGI RRKRLKGDAF MYKKVCEKIL QMAKIE
