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Protein

MAP/microtubule affinity-regulating kinase 4

Gene

MARK4

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Serine/threonine-protein kinase (PubMed:15009667, PubMed:14594945, PubMed:23666762, PubMed:23184942). Phosphorylates the microtubule-associated protein MAPT (PubMed:14594945, PubMed:23666762). Also phosphorylates the microtubule-associated proteins MAP2 and MAP4 (PubMed:14594945). Involved in regulation of the microtubule network, causing reorganization of microtubules into bundles (PubMed:14594945, PubMed:25123532). Required for the initiation of axoneme extension during cilium assembly (PubMed:23400999). Regulates the centrosomal location of ODF2 and phosphorylates ODF2 in vitro (PubMed:23400999). Plays a role in cell cycle progression, specifically in the G1/S checkpoint (PubMed:25123532). Reduces neuronal cell survival (PubMed:15009667). Plays a role in energy homeostasis by regulating satiety and metabolic rate (By similarity). Promotes adipogenesis by activating JNK1 and inhibiting the p38MAPK pathway, and triggers apoptosis by activating the JNK1 pathway (By similarity). Phosphorylates mTORC1 complex member RPTOR and acts as a negative regulator of the mTORC1 complex, probably due to disruption of the interaction between phosphorylated RPTOR and the RRAGA/RRAGC heterodimer which is required for mTORC1 activation (PubMed:23184942).By similarity6 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.3 Publications

Cofactori

Mg2+1 Publication

Enzyme regulationi

Activated by phosphorylation on Thr-214.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei88ATPPROSITE-ProRule annotation1
Active sitei181Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi65 – 73ATPPROSITE-ProRule annotation9

GO - Molecular functioni

  • ATP binding Source: UniProtKB
  • gamma-tubulin binding Source: UniProtKB
  • microtubule binding Source: UniProtKB
  • protein serine/threonine kinase activity Source: UniProtKB
  • tau-protein kinase activity Source: UniProtKB
  • ubiquitin binding Source: UniProtKB

GO - Biological processi

  • cell division Source: UniProtKB-KW
  • cell projection organization Source: UniProtKB-KW
  • establishment of cell polarity Source: InterPro
  • microtubule bundle formation Source: UniProtKB
  • microtubule cytoskeleton organization Source: UniProtKB
  • mitotic nuclear division Source: UniProtKB-KW
  • nervous system development Source: UniProtKB
  • positive regulation of programmed cell death Source: UniProtKB
  • protein phosphorylation Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Biological processi

Cell cycle, Cell division, Cilium biogenesis/degradation, Mitosis

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

BioCyciZFISH:HS00202-MONOMER.
ReactomeiR-HSA-5620912. Anchoring of the basal body to the plasma membrane.
SignaLinkiQ96L34.
SIGNORiQ96L34.

Names & Taxonomyi

Protein namesi
Recommended name:
MAP/microtubule affinity-regulating kinase 4 (EC:2.7.11.13 Publications)
Alternative name(s):
MAP/microtubule affinity-regulating kinase-like 1
Gene namesi
Name:MARK4
Synonyms:KIAA1860, MARKL1
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 19

Organism-specific databases

HGNCiHGNC:13538. MARK4.

Subcellular locationi

GO - Cellular componenti

  • centrosome Source: UniProtKB
  • ciliary basal body Source: CACAO
  • cytosol Source: Reactome
  • microtubule cytoskeleton Source: UniProtKB
  • microtubule organizing center Source: UniProtKB
  • neuron projection Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cell projection, Cytoplasm, Cytoskeleton

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi214T → A: Prevents phosphorylation and activation by STK11/LKB1 complex. 1 Publication1
Mutagenesisi214T → E: Mimicks phosphorylation state, leading to increased activity. Decreases mTORC1 activity. 2 Publications1

Organism-specific databases

DisGeNETi57787.
OpenTargetsiENSG00000007047.
PharmGKBiPA30641.

Chemistry databases

ChEMBLiCHEMBL5754.
GuidetoPHARMACOLOGYi2100.

Polymorphism and mutation databases

BioMutaiMARK4.
DMDMi29840797.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000863071 – 752MAP/microtubule affinity-regulating kinase 4Add BLAST752

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei214Phosphothreonine; by LKB11 Publication1
Modified residuei423PhosphoserineBy similarity1
Modified residuei543PhosphoserineCombined sources1

Post-translational modificationi

Ubiquitinated with 'Lys-29'- and 'Lys-33'-linked polyubiquitins which appear to impede LKB1-mediated phosphorylation. Deubiquitinated by USP9X.2 Publications
Phosphorylated at Thr-214 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39 (PubMed:14976552). Phosphorylated throughout the cell cycle (PubMed:25123532).2 Publications

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiQ96L34.
MaxQBiQ96L34.
PaxDbiQ96L34.
PeptideAtlasiQ96L34.
PRIDEiQ96L34.

PTM databases

iPTMnetiQ96L34.
PhosphoSitePlusiQ96L34.

Expressioni

Tissue specificityi

Ubiquitous. Isoform 2 is brain-specific (PubMed:11326310). Expressed at highest levels in brain and testis. Also expressed in heart, lung, liver, muscle, kidney and spleen (PubMed:14594945).2 Publications

Developmental stagei

Expressed at all stages of the mitotic cell cycle.1 Publication

Gene expression databases

BgeeiENSG00000007047.
CleanExiHS_MARK4.
ExpressionAtlasiQ96L34. baseline and differential.
GenevisibleiQ96L34. HS.

Organism-specific databases

HPAiHPA039186.

Interactioni

Subunit structurei

Interacts with gamma-tubulin (PubMed:14594945). Interacts with ODF2 (PubMed:23400999). Interacts with USP9X (PubMed:18254724).3 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
CDC42P609532EBI-302319,EBI-81752
PARD6GQ9BYG42EBI-302319,EBI-295417
PNMA1Q8ND902EBI-302319,EBI-302345
PRKCIP417432EBI-302319,EBI-286199
STK11Q158312EBI-302319,EBI-306838
TUBG1P232584EBI-302319,EBI-302589
YWHAHQ049176EBI-302319,EBI-306940

GO - Molecular functioni

  • gamma-tubulin binding Source: UniProtKB
  • microtubule binding Source: UniProtKB
  • ubiquitin binding Source: UniProtKB

Protein-protein interaction databases

BioGridi121760. 50 interactors.
IntActiQ96L34. 29 interactors.
MINTiMINT-6425023.
STRINGi9606.ENSP00000262891.

Chemistry databases

BindingDBiQ96L34.

Structurei

Secondary structure

1752
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi59 – 67Combined sources9
Beta strandi69 – 78Combined sources10
Turni79 – 81Combined sources3
Beta strandi84 – 91Combined sources8
Helixi92 – 94Combined sources3
Helixi97 – 111Combined sources15
Beta strandi121 – 126Combined sources6
Beta strandi128 – 135Combined sources8
Helixi143 – 150Combined sources8
Helixi155 – 174Combined sources20
Beta strandi186 – 189Combined sources4
Beta strandi195 – 197Combined sources3
Turni219 – 221Combined sources3
Helixi224 – 228Combined sources5
Helixi235 – 251Combined sources17
Helixi261 – 270Combined sources10
Helixi281 – 290Combined sources10
Turni295 – 297Combined sources3
Helixi301 – 304Combined sources4
Helixi308 – 311Combined sources4
Helixi332 – 339Combined sources8
Turni340 – 342Combined sources3
Helixi345 – 352Combined sources8
Turni353 – 355Combined sources3
Helixi359 – 366Combined sources8
Turni367 – 369Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
5ES1X-ray2.80A44-370[»]
ProteinModelPortaliQ96L34.
SMRiQ96L34.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini59 – 310Protein kinasePROSITE-ProRule annotationAdd BLAST252
Domaini324 – 368UBAPROSITE-ProRule annotationAdd BLAST45
Domaini703 – 752KA1PROSITE-ProRule annotationAdd BLAST50

Sequence similaritiesi

Contains 1 KA1 (kinase-associated) domain.PROSITE-ProRule annotation
Contains 1 protein kinase domain.PROSITE-ProRule annotation
Contains 1 UBA domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiKOG0586. Eukaryota.
ENOG410XNQ0. LUCA.
GeneTreeiENSGT00790000122947.
HOGENOMiHOG000233025.
HOVERGENiHBG052453.
InParanoidiQ96L34.
KOiK08798.
OMAiLAHEATP.
OrthoDBiEOG091G0D1E.
PhylomeDBiQ96L34.
TreeFamiTF315213.

Family and domain databases

Gene3Di3.30.310.80. 1 hit.
InterProiIPR028375. KA1/Ssp2_C.
IPR001772. KA1_dom.
IPR011009. Kinase-like_dom.
IPR033624. MARK/par1.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
IPR015940. UBA.
[Graphical view]
PANTHERiPTHR24346. PTHR24346. 1 hit.
PfamiPF02149. KA1. 1 hit.
PF00069. Pkinase. 1 hit.
PF00627. UBA. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
SM00165. UBA. 1 hit.
[Graphical view]
SUPFAMiSSF103243. SSF103243. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEiPS50032. KA1. 1 hit.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
PS50030. UBA. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q96L34-1) [UniParc]FASTAAdd to basket
Also known as: MARK4L

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MSSRTVLAPG NDRNSDTHGT LGSGRSSDKG PSWSSRSLGA RCRNSIASCP
60 70 80 90 100
EEQPHVGNYR LLRTIGKGNF AKVKLARHIL TGREVAIKII DKTQLNPSSL
110 120 130 140 150
QKLFREVRIM KGLNHPNIVK LFEVIETEKT LYLVMEYASA GEVFDYLVSH
160 170 180 190 200
GRMKEKEARA KFRQIVSAVH YCHQKNIVHR DLKAENLLLD AEANIKIADF
210 220 230 240 250
GFSNEFTLGS KLDTFCGSPP YAAPELFQGK KYDGPEVDIW SLGVILYTLV
260 270 280 290 300
SGSLPFDGHN LKELRERVLR GKYRVPFYMS TDCESILRRF LVLNPAKRCT
310 320 330 340 350
LEQIMKDKWI NIGYEGEELK PYTEPEEDFG DTKRIEVMVG MGYTREEIKE
360 370 380 390 400
SLTSQKYNEV TATYLLLGRK TEEGGDRGAP GLALARVRAP SDTTNGTSSS
410 420 430 440 450
KGTSHSKGQR SSSSTYHRQR RHSDFCGPSP APLHPKRSPT STGEAELKEE
460 470 480 490 500
RLPGRKASCS TAGSGSRGLP PSSPMVSSAH NPNKAEIPER RKDSTSTPNN
510 520 530 540 550
LPPSMMTRRN TYVCTERPGA ERPSLLPNGK ENSSGTPRVP PASPSSHSLA
560 570 580 590 600
PPSGERSRLA RGSTIRSTFH GGQVRDRRAG GGGGGGVQNG PPASPTLAHE
610 620 630 640 650
AAPLPAGRPR PTTNLFTKLT SKLTRRVADE PERIGGPEVT SCHLPWDQTE
660 670 680 690 700
TAPRLLRFPW SVKLTSSRPP EALMAALRQA TAAARCRCRQ PQPFLLACLH
710 720 730 740 750
GGAGGPEPLS HFEVEVCQLP RPGLRGVLFR RVAGTALAFR TLVTRISNDL

EL
Length:752
Mass (Da):82,520
Last modified:December 1, 2001 - v1
Checksum:i4B430FFD2B150E7A
GO
Isoform 2 (identifier: Q96L34-2) [UniParc]FASTAAdd to basket
Also known as: MARKL1S, MARK4S

The sequence of this isoform differs from the canonical sequence as follows:
     628-752: ADEPERIGGP...VTRISNDLEL → TLDPSKRQNS...PPGCSDSPGV

Show »
Length:688
Mass (Da):75,321
Checksum:iA49143B34FDDD086
GO

Sequence cautioni

The sequence BAB47489 differs from that shown. Reason: Erroneous initiation.Curated
The sequence BAB55238 differs from that shown. Reason: Erroneous initiation.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti70F → S in BAB39380 (PubMed:11326310).Curated1
Sequence conflicti70F → S in BAC03375 (PubMed:11326310).Curated1
Sequence conflicti518P → L in BAB55238 (PubMed:14702039).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_040766377R → Q.1 PublicationCorresponds to variant rs35070611dbSNPEnsembl.1
Natural variantiVAR_040767418R → C in a colorectal adenocarcinoma sample; somatic mutation. 1 PublicationCorresponds to variant rs780763668dbSNPEnsembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_004946628 – 752ADEPE…NDLEL → TLDPSKRQNSNRCVSGASLP QGSKIRSQTNLRESGDLRSQ VAIYLGIKRKPPPGCSDSPG V in isoform 2. 2 PublicationsAdd BLAST125

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB049127 mRNA. Translation: BAB39380.1.
AB088047 mRNA. Translation: BAC03375.1.
AY057448 mRNA. Translation: AAL23683.1.
AX305105 mRNA. No translation available.
AX305106 mRNA. No translation available.
AY120867 mRNA. Translation: AAM55491.1.
AB058763 mRNA. Translation: BAB47489.1. Different initiation.
AK027619 mRNA. Translation: BAB55238.1. Different initiation.
AK075272 mRNA. Translation: BAC11510.1.
CCDSiCCDS12658.1. [Q96L34-2]
CCDS56097.1. [Q96L34-1]
RefSeqiNP_001186796.1. NM_001199867.1. [Q96L34-1]
NP_113605.2. NM_031417.3. [Q96L34-2]
UniGeneiHs.34314.

Genome annotation databases

EnsembliENST00000262891; ENSP00000262891; ENSG00000007047. [Q96L34-1]
ENST00000300843; ENSP00000300843; ENSG00000007047. [Q96L34-2]
GeneIDi57787.
KEGGihsa:57787.
UCSCiuc002pba.3. human. [Q96L34-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Web resourcesi

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB049127 mRNA. Translation: BAB39380.1.
AB088047 mRNA. Translation: BAC03375.1.
AY057448 mRNA. Translation: AAL23683.1.
AX305105 mRNA. No translation available.
AX305106 mRNA. No translation available.
AY120867 mRNA. Translation: AAM55491.1.
AB058763 mRNA. Translation: BAB47489.1. Different initiation.
AK027619 mRNA. Translation: BAB55238.1. Different initiation.
AK075272 mRNA. Translation: BAC11510.1.
CCDSiCCDS12658.1. [Q96L34-2]
CCDS56097.1. [Q96L34-1]
RefSeqiNP_001186796.1. NM_001199867.1. [Q96L34-1]
NP_113605.2. NM_031417.3. [Q96L34-2]
UniGeneiHs.34314.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
5ES1X-ray2.80A44-370[»]
ProteinModelPortaliQ96L34.
SMRiQ96L34.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi121760. 50 interactors.
IntActiQ96L34. 29 interactors.
MINTiMINT-6425023.
STRINGi9606.ENSP00000262891.

Chemistry databases

BindingDBiQ96L34.
ChEMBLiCHEMBL5754.
GuidetoPHARMACOLOGYi2100.

PTM databases

iPTMnetiQ96L34.
PhosphoSitePlusiQ96L34.

Polymorphism and mutation databases

BioMutaiMARK4.
DMDMi29840797.

Proteomic databases

EPDiQ96L34.
MaxQBiQ96L34.
PaxDbiQ96L34.
PeptideAtlasiQ96L34.
PRIDEiQ96L34.

Protocols and materials databases

DNASUi57787.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000262891; ENSP00000262891; ENSG00000007047. [Q96L34-1]
ENST00000300843; ENSP00000300843; ENSG00000007047. [Q96L34-2]
GeneIDi57787.
KEGGihsa:57787.
UCSCiuc002pba.3. human. [Q96L34-1]

Organism-specific databases

CTDi57787.
DisGeNETi57787.
GeneCardsiMARK4.
HGNCiHGNC:13538. MARK4.
HPAiHPA039186.
MIMi606495. gene.
neXtProtiNX_Q96L34.
OpenTargetsiENSG00000007047.
PharmGKBiPA30641.
HUGEiSearch...
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0586. Eukaryota.
ENOG410XNQ0. LUCA.
GeneTreeiENSGT00790000122947.
HOGENOMiHOG000233025.
HOVERGENiHBG052453.
InParanoidiQ96L34.
KOiK08798.
OMAiLAHEATP.
OrthoDBiEOG091G0D1E.
PhylomeDBiQ96L34.
TreeFamiTF315213.

Enzyme and pathway databases

BioCyciZFISH:HS00202-MONOMER.
ReactomeiR-HSA-5620912. Anchoring of the basal body to the plasma membrane.
SignaLinkiQ96L34.
SIGNORiQ96L34.

Miscellaneous databases

GeneWikiiMARK4.
GenomeRNAii57787.
PROiQ96L34.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000007047.
CleanExiHS_MARK4.
ExpressionAtlasiQ96L34. baseline and differential.
GenevisibleiQ96L34. HS.

Family and domain databases

Gene3Di3.30.310.80. 1 hit.
InterProiIPR028375. KA1/Ssp2_C.
IPR001772. KA1_dom.
IPR011009. Kinase-like_dom.
IPR033624. MARK/par1.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
IPR015940. UBA.
[Graphical view]
PANTHERiPTHR24346. PTHR24346. 1 hit.
PfamiPF02149. KA1. 1 hit.
PF00069. Pkinase. 1 hit.
PF00627. UBA. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
SM00165. UBA. 1 hit.
[Graphical view]
SUPFAMiSSF103243. SSF103243. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEiPS50032. KA1. 1 hit.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
PS50030. UBA. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiMARK4_HUMAN
AccessioniPrimary (citable) accession number: Q96L34
Secondary accession number(s): Q8NG37
, Q96JG7, Q96SQ2, Q9BYD8
Entry historyi
Integrated into UniProtKB/Swiss-Prot: February 28, 2003
Last sequence update: December 1, 2001
Last modified: November 2, 2016
This is version 159 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 19
    Human chromosome 19: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  7. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.