MARK4_MOUSE
ID MARK4_MOUSE Reviewed; 752 AA.
AC Q8CIP4; Q80T81;
DT 08-NOV-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 03-AUG-2022, entry version 154.
DE RecName: Full=MAP/microtubule affinity-regulating kinase 4;
DE EC=2.7.11.1 {ECO:0000250|UniProtKB:Q96L34};
GN Name=Mark4; Synonyms=Kiaa1860;
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] (ISOFORM 1), AND TISSUE SPECIFICITY.
RX PubMed=16973293; DOI=10.1016/j.neuroscience.2006.07.052;
RA Moroni R.F., De Biasi S., Colapietro P., Larizza L., Beghini A.;
RT "Distinct expression pattern of microtubule-associated protein/microtubule
RT affinity-regulating kinase 4 in differentiated neurons.";
RL Neuroscience 143:83-94(2006).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 29-752 (ISOFORMS 1 AND 2), AND TISSUE
RP SPECIFICITY.
RX PubMed=15009667; DOI=10.1046/j.1471-4159.2003.02228.x;
RA Schneider A., Laage R., von Ahsen O., Fischer A., Rossner M., Scheek S.,
RA Grunewald S., Kuner R., Weber D., Kruger C., Klaussner B., Gotz B.,
RA Hiemisch H., Newrzella D., Martin-Villalba A., Bach A., Schwaninger M.;
RT "Identification of regulated genes during permanent focal cerebral
RT ischaemia: characterization of the protein kinase 9b5/MARKL1/MARK4.";
RL J. Neurochem. 88:1114-1126(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 119-752 (ISOFORM 1).
RC TISSUE=Pancreatic islet;
RX PubMed=12693553; DOI=10.1093/dnares/10.1.35;
RA Okazaki N., Kikuno R., Ohara R., Inamoto S., Aizawa H., Yuasa S.,
RA Nakajima D., Nagase T., Ohara O., Koga H.;
RT "Prediction of the coding sequences of mouse homologues of KIAA gene: II.
RT The complete nucleotide sequences of 400 mouse KIAA-homologous cDNAs
RT identified by screening of terminal sequences of cDNA clones randomly
RT sampled from size-fractionated libraries.";
RL DNA Res. 10:35-48(2003).
RN [4]
RP SEQUENCE REVISION.
RA Okazaki N., Kikuno R., Nagase T., Ohara O., Koga H.;
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP PROTEIN SEQUENCE OF 299-308, AND IDENTIFICATION BY MASS SPECTROMETRY.
RC STRAIN=OF1; TISSUE=Hippocampus;
RA Lubec G., Sunyer B., Chen W.-Q.;
RL Submitted (JAN-2009) to UniProtKB.
RN [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-423, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain;
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).
RN [7]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=22992738; DOI=10.1074/jbc.m112.388934;
RA Sun C., Tian L., Nie J., Zhang H., Han X., Shi Y.;
RT "Inactivation of MARK4, an AMP-activated protein kinase (AMPK)-related
RT kinase, leads to insulin hypersensitivity and resistance to diet-induced
RT obesity.";
RL J. Biol. Chem. 287:38305-38315(2012).
RN [8]
RP FUNCTION.
RX PubMed=24989893; DOI=10.1111/boc.201400004;
RA Feng M., Tian L., Gan L., Liu Z., Sun C.;
RT "Mark4 promotes adipogenesis and triggers apoptosis in 3T3-L1 adipocytes by
RT activating JNK1 and inhibiting p38MAPK pathways.";
RL Biol. Cell 106:294-307(2014).
CC -!- FUNCTION: Serine/threonine-protein kinase (By similarity).
CC Phosphorylates the microtubule-associated protein MAPT/TAU (By
CC similarity). Also phosphorylates the microtubule-associated proteins
CC MAP2 and MAP4 (By similarity). Involved in regulation of the
CC microtubule network, causing reorganization of microtubules into
CC bundles (By similarity). Required for the initiation of axoneme
CC extension during cilium assembly (By similarity). Regulates the
CC centrosomal location of ODF2 and phosphorylates ODF2 in vitro (By
CC similarity). Plays a role in cell cycle progression, specifically in
CC the G1/S checkpoint (By similarity). Reduces neuronal cell survival (By
CC similarity). Plays a role in energy homeostasis by regulating satiety
CC and metabolic rate (PubMed:22992738). Promotes adipogenesis by
CC activating JNK1 and inhibiting the p38MAPK pathway, and triggers
CC apoptosis by activating the JNK1 pathway (PubMed:24989893).
CC Phosphorylates mTORC1 complex member RPTOR and acts as a negative
CC regulator of the mTORC1 complex, probably due to disruption of the
CC interaction between phosphorylated RPTOR and the RRAGA/RRAGC
CC heterodimer which is required for mTORC1 activation (By similarity).
CC {ECO:0000250|UniProtKB:Q96L34, ECO:0000269|PubMed:22992738,
CC ECO:0000269|PubMed:24989893}.
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:Q96L34};
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:Q96L34};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:Q96L34};
CC -!- ACTIVITY REGULATION: Activated by phosphorylation on Thr-214.
CC {ECO:0000250|UniProtKB:Q96L34}.
CC -!- SUBUNIT: Interacts with MAPT/TAU. Interacts with gamma-tubulin.
CC Interacts with ODF2. Interacts with USP9X. Interacts with YWHAQ (By
CC similarity). {ECO:0000250|UniProtKB:Q96L34}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton, microtubule organizing
CC center, centrosome {ECO:0000250|UniProtKB:Q96L34}. Cytoplasm,
CC cytoskeleton, microtubule organizing center
CC {ECO:0000250|UniProtKB:Q96L34}. Cytoplasm, cytoskeleton, cilium axoneme
CC {ECO:0000250|UniProtKB:Q96L34}. Cytoplasm, cytoskeleton, cilium basal
CC body {ECO:0000250|UniProtKB:Q96L34}. Cytoplasm
CC {ECO:0000250|UniProtKB:Q96L34}. Cell projection, dendrite
CC {ECO:0000250|UniProtKB:Q96L34}. Note=Localized at the tips of neurite-
CC like processes in differentiated neuroblast cells. Detected in the
CC cytoplasm and neuropil of the hippocampus.
CC {ECO:0000250|UniProtKB:Q96L34}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=MARK4L;
CC IsoId=Q8CIP4-1; Sequence=Displayed;
CC Name=2; Synonyms=MARK4S;
CC IsoId=Q8CIP4-2; Sequence=VSP_058199;
CC -!- TISSUE SPECIFICITY: Isoform 1 and isoform 2 show similar expression
CC patterns in the central nervous system and are present in the same
CC subsets of neurons including pyramidal and non-pyramidal neurons in the
CC cerebral cortex and hippocampus, cerebellar Purkinje cells, and
CC interneurons and motor neurons in the spinal cord but not in glial
CC cells (at protein level) (PubMed:16973293). Isoform 2 is the major
CC isoform in brain and cerebellum (PubMed:16973293, PubMed:15009667).
CC Also expressed in spleen, liver, small intestine, colon, kidney,
CC tongue, testis and lung (PubMed:16973293, PubMed:15009667). Isoform 1
CC and isoform 2 are expressed at similar levels in heart
CC (PubMed:16973293). {ECO:0000269|PubMed:15009667,
CC ECO:0000269|PubMed:16973293}.
CC -!- PTM: Ubiquitinated with 'Lys-29'- and 'Lys-33'-linked polyubiquitins
CC which appear to impede LKB1-mediated phosphorylation. Deubiquitinated
CC by USP9X (By similarity). {ECO:0000250|UniProtKB:Q96L34}.
CC -!- PTM: Phosphorylated at Thr-214 by STK11/LKB1 in complex with STE20-
CC related adapter-alpha (STRADA) pseudo kinase and CAB39. Phosphorylated
CC throughout the cell cycle. {ECO:0000250|UniProtKB:Q96L34}.
CC -!- DISRUPTION PHENOTYPE: Hyperphagia, hyperactivity and hypermetabolism
CC leading to protection from diet-induced obesity, and improved glucose
CC homeostasis due to up-regulation of AMPK kinase activity.
CC {ECO:0000269|PubMed:22992738}.
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; AY151083; AAN60072.1; -; mRNA.
DR EMBL; AX305103; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AX305104; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AK122565; BAC65847.2; -; mRNA.
DR CCDS; CCDS20903.1; -. [Q8CIP4-1]
DR RefSeq; NP_758483.1; NM_172279.1. [Q8CIP4-1]
DR RefSeq; XP_006539892.1; XM_006539829.3.
DR AlphaFoldDB; Q8CIP4; -.
DR SMR; Q8CIP4; -.
DR BioGRID; 231328; 21.
DR DIP; DIP-60721N; -.
DR IntAct; Q8CIP4; 4.
DR STRING; 10090.ENSMUSP00000082862; -.
DR BindingDB; Q8CIP4; -.
DR ChEMBL; CHEMBL4523387; -.
DR iPTMnet; Q8CIP4; -.
DR PhosphoSitePlus; Q8CIP4; -.
DR EPD; Q8CIP4; -.
DR jPOST; Q8CIP4; -.
DR MaxQB; Q8CIP4; -.
DR PaxDb; Q8CIP4; -.
DR PeptideAtlas; Q8CIP4; -.
DR PRIDE; Q8CIP4; -.
DR ProteomicsDB; 295796; -. [Q8CIP4-1]
DR ProteomicsDB; 295797; -. [Q8CIP4-2]
DR Antibodypedia; 31285; 387 antibodies from 37 providers.
DR DNASU; 232944; -.
DR Ensembl; ENSMUST00000085715; ENSMUSP00000082862; ENSMUSG00000030397. [Q8CIP4-1]
DR Ensembl; ENSMUST00000239292; ENSMUSP00000159279; ENSMUSG00000030397. [Q8CIP4-2]
DR GeneID; 232944; -.
DR KEGG; mmu:232944; -.
DR UCSC; uc009flx.1; mouse. [Q8CIP4-1]
DR CTD; 57787; -.
DR MGI; MGI:1920955; Mark4.
DR VEuPathDB; HostDB:ENSMUSG00000030397; -.
DR eggNOG; KOG0586; Eukaryota.
DR GeneTree; ENSGT00940000159555; -.
DR HOGENOM; CLU_000288_157_5_1; -.
DR InParanoid; Q8CIP4; -.
DR OMA; CHLPWDK; -.
DR OrthoDB; 1127668at2759; -.
DR PhylomeDB; Q8CIP4; -.
DR TreeFam; TF315213; -.
DR Reactome; R-MMU-5620912; Anchoring of the basal body to the plasma membrane.
DR BioGRID-ORCS; 232944; 2 hits in 77 CRISPR screens.
DR ChiTaRS; Mark4; mouse.
DR PRO; PR:Q8CIP4; -.
DR Proteomes; UP000000589; Chromosome 7.
DR RNAct; Q8CIP4; protein.
DR Bgee; ENSMUSG00000030397; Expressed in internal carotid artery and 242 other tissues.
DR ExpressionAtlas; Q8CIP4; baseline and differential.
DR Genevisible; Q8CIP4; MM.
DR GO; GO:0005813; C:centrosome; ISS:UniProtKB.
DR GO; GO:0036064; C:ciliary basal body; ISO:MGI.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0030425; C:dendrite; ISS:UniProtKB.
DR GO; GO:0000930; C:gamma-tubulin complex; ISO:MGI.
DR GO; GO:0015630; C:microtubule cytoskeleton; ISS:UniProtKB.
DR GO; GO:0005815; C:microtubule organizing center; ISS:UniProtKB.
DR GO; GO:0030496; C:midbody; ISO:MGI.
DR GO; GO:0043005; C:neuron projection; ISS:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0043015; F:gamma-tubulin binding; ISS:UniProtKB.
DR GO; GO:0008017; F:microtubule binding; ISS:UniProtKB.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; ISS:UniProtKB.
DR GO; GO:0050321; F:tau-protein kinase activity; ISS:UniProtKB.
DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR GO; GO:0051301; P:cell division; IEA:UniProtKB-KW.
DR GO; GO:0044782; P:cilium organization; ISO:MGI.
DR GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central.
DR GO; GO:0001578; P:microtubule bundle formation; ISS:UniProtKB.
DR GO; GO:0000226; P:microtubule cytoskeleton organization; ISS:UniProtKB.
DR GO; GO:0007399; P:nervous system development; ISS:UniProtKB.
DR GO; GO:0045787; P:positive regulation of cell cycle; ISO:MGI.
DR GO; GO:0045724; P:positive regulation of cilium assembly; ISO:MGI.
DR GO; GO:1904781; P:positive regulation of protein localization to centrosome; ISO:MGI.
DR GO; GO:0006468; P:protein phosphorylation; ISS:UniProtKB.
DR GO; GO:0046605; P:regulation of centrosome cycle; ISO:MGI.
DR InterPro; IPR028375; KA1/Ssp2_C.
DR InterPro; IPR001772; KA1_dom.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR InterPro; IPR015940; UBA.
DR Pfam; PF02149; KA1; 1.
DR Pfam; PF00069; Pkinase; 1.
DR Pfam; PF00627; UBA; 1.
DR SMART; SM00220; S_TKc; 1.
DR SMART; SM00165; UBA; 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.
DR PROSITE; PS50030; UBA; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; ATP-binding; Cell cycle; Cell division;
KW Cell projection; Cilium biogenesis/degradation; Cytoplasm; Cytoskeleton;
KW Direct protein sequencing; Kinase; Mitosis; Nucleotide-binding;
KW Phosphoprotein; Reference proteome; Serine/threonine-protein kinase;
KW Transferase; Ubl conjugation.
FT CHAIN 1..752
FT /note="MAP/microtubule affinity-regulating kinase 4"
FT /id="PRO_0000086308"
FT DOMAIN 59..310
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT DOMAIN 324..368
FT /note="UBA"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00212"
FT DOMAIN 703..752
FT /note="KA1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00565"
FT REGION 1..36
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 385..615
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 390..413
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 441..455
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 465..480
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 494..514
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 526..552
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 181
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 65..73
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 88
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 214
FT /note="Phosphothreonine; by LKB1"
FT /evidence="ECO:0000250|UniProtKB:Q96L34"
FT MOD_RES 423
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 543
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q96L34"
FT VAR_SEQ 628..752
FT /note="TDEPERIGGPEVTSCHLPWDKTETAPRLLRFPWSVKLTSSRPPEALMAALRQ
FT ATAAARCRCRQPQPFLLACLHGGAGGPEPLSHFEVEVCQLPRPGLRGVLFRRVAGTALA
FT FRTLVTRISNDLEL -> TLDPSKRQNSNRCVSGASLPQGSKIRSQTNLRESGDLRSQV
FT AIYLGIKRKPPPGCSDSPGV (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15009667"
FT /id="VSP_058199"
FT CONFLICT 162
FT /note="F -> L (in Ref. 2; AX305103/AX305104)"
FT /evidence="ECO:0000305"
FT CONFLICT 268
FT /note="V -> I (in Ref. 2; AX305103/AX305104)"
FT /evidence="ECO:0000305"
FT CONFLICT 372
FT /note="E -> D (in Ref. 2; AX305103/AX305104)"
FT /evidence="ECO:0000305"
FT CONFLICT 438
FT /note="S -> T (in Ref. 2; AX305103)"
FT /evidence="ECO:0000305"
FT CONFLICT 677
FT /note="L -> M (in Ref. 2; AX305103)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 752 AA; 82644 MW; 185FDAE3F0D627DD CRC64;
MSSRTALAPG NDRNSDTHGT LGSGRSSDKG PSWSSRSLGA RCRNSIASCP EEQPHVGNYR
LLRTIGKGNF AKVKLARHIL TGREVAIKII DKTQLNPSSL QKLFREVRIM KGLNHPNIVK
LFEVIETEKT LYLVMEYASA GEVFDYLVSH GRMKEKEARA KFRQIVSAVH YCHQKNIVHR
DLKAENLLLD AEANIKIADF GFSNEFTLGS KLDTFCGSPP YAAPELFQGK KYDGPEVDIW
SLGVILYTLV SGSLPFDGHN LKELRERVLR GKYRVPFYMS TDCESILRRF LVLNPAKRCT
LEQIMKDKWI NIGYEGEELK PYTEPEEDFG DTKRIEVMVG MGYTREEIKE ALTNQKYNEV
TATYLLLGRK TEEGGDRGAP GLALARVRAP SDTTNGTSSS KGSSHNKGQR ASSSTYHRQR
RHSDFCGPSP APLHPKRSPT STGDTELKEE RMPGRKASCS AVGSGSRGLP PSSPMVSSAH
NPNKAEIPER RKDSTSTPNN LPPSMMTRRN TYVCTERPGS ERPSLLPNGK ENSSGTSRVP
PASPSSHSLA PPSGERSRLA RGSTIRSTFH GGQVRDRRAG SGSGGGVQNG PPASPTLAHE
AAPLPSGRPR PTTNLFTKLT SKLTRRVTDE PERIGGPEVT SCHLPWDKTE TAPRLLRFPW
SVKLTSSRPP EALMAALRQA TAAARCRCRQ PQPFLLACLH GGAGGPEPLS HFEVEVCQLP
RPGLRGVLFR RVAGTALAFR TLVTRISNDL EL
