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O08679 (MARK2_RAT) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 117. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (2) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Serine/threonine-protein kinase MARK2

EC=2.7.11.1
EC=2.7.11.26
Alternative name(s):
ELKL motif kinase 1
Short name=EMK-1
MAP/microtubule affinity-regulating kinase 2
Gene names
Name:Mark2
OrganismRattus norvegicus (Rat) [Reference proteome]
Taxonomic identifier10116 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus

Protein attributes

Sequence length722 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Serine/threonine-protein kinase involved in cell polarity and microtubule dynamics regulation. Phosphorylates CRTC2/TORC2, DCX, HDAC7, KIF13B, MAP2, MAP4, MAPT/TAU and RAB11FIP2. Plays a key role in cell polarity by phosphorylating the microtubule-associated proteins MAP2, MAP4 and MAPT/TAU at KXGS motifs, causing detachment from microtubules, and their disassembly. Regulates epithelial cell polarity by phosphorylating RAB11FIP2. Involved in the regulation of neuronal migration through its dual activities in regulating cellular polarity and microtubule dynamics, possibly by phosphorylating and regulating DCX. Regulates axogenesis by phosphorylating KIF13B, promoting interaction between KIF13B and 14-3-3 and inhibiting microtubule-dependent accumulation of KIF13B. Also required for neurite outgrowth and establishment of neuronal polarity. Regulates localization and activity of some histone deacetylases by mediating phosphorylation of HDAC7, promoting subsequent interaction between HDAC7 and 14-3-3 and export from the nucleus. Also acts as a positive regulator of the Wnt signaling pathway, probably by mediating phosphorylation of dishevelled proteins (DVL1, DVL2 and/or DVL3). Modulates the developmental decision to build a columnar versus a hepatic epithelial cell apparently by promoting a switch from a direct to a transcytotic mode of apical protein delivery. Essential for the asymmetric development of membrane domains of polarized epithelial cells. Ref.2 Ref.3 Ref.4 Ref.7 Ref.10

Catalytic activity

ATP + a protein = ADP + a phosphoprotein. UniProtKB Q7KZI7

ATP + [tau protein] = ADP + [tau protein] phosphate.

Cofactor

Magnesium By similarity. UniProtKB Q7KZI7

Enzyme regulation

Inhibited by hymenialdisine By similarity. Activated by phosphorylation on Thr-208 by STK11/LKB1 and TAOK1. Inhibited by phosphorylation at Ser-212 or Thr-539. Inhibited by PAK7/PAK5; inhibition is independent of the kinase activity of PAK7/PAK5. Ref.2

Subunit structure

Homodimer. Interacts (when phosphorylated at Thr-539) with YWHAZ. Interacts with MTCL1; the interaction is direct and increases MARK2 microtubule-binding ability By similarity. Interacts with PAK7/PAK5; leading to inhibit the protein kinase activity. Ref.6 Ref.11

Subcellular location

Cell membrane; Peripheral membrane protein. Cytoplasm By similarity. Lateral cell membrane By similarity. Cytoplasmcytoskeleton By similarity. Note: Phosphorylation at Thr-539 by PRKCZ/aPKC and subsequent interaction with 14-3-3 protein YWHAZ promotes relocation from the cell membrane to the cytoplasm By similarity. Ref.4

Domain

The KA1 domain mediates binding to phospholipids and targeting to membranes By similarity.

The UBA domain does not seem to bind ubiquitin and ubiquitin-like and might play a role in regulating the enzyme conformation and localization. Activation of the kinase activity following phosphorylation at Thr-208 is accompanied by a conformational change that alters the orientation of the UBA domain with respect to the catalytic domain By similarity.

Post-translational modification

Autophosphorylated. Phosphorylated at Thr-208 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39. Phosphorylation at Thr-208 by TAOK1 activates the kinase activity, leading to phosphorylation and detachment of MAPT/TAU from microtubules. Phosphorylation at Ser-212 by GSK3-beta (GSK3B) inhibits the kinase activity. Phosphorylation by CaMK1 promotes activity and is required to promote neurite outgrowth. Phosphorylation at Thr-539 by PRKCZ/aPKC in polarized epithelial cells inhibits the kinase activity and promotes binding to 14-3-3 protein YWHAZ, leading to relocation from cell membrane to cytoplasm. Ref.2 Ref.5 Ref.7 Ref.8 Ref.9

Sequence similarities

Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. SNF1 subfamily.

Contains 1 KA1 (kinase-associated) domain.

Contains 1 protein kinase domain.

Contains 1 UBA domain.

Ontologies

Keywords
   Biological processDifferentiation
Wnt signaling pathway
   Cellular componentCell membrane
Cytoplasm
Cytoskeleton
Membrane
   LigandATP-binding
Lipid-binding
Magnesium
Metal-binding
Nucleotide-binding
   Molecular functionDevelopmental protein
Kinase
Serine/threonine-protein kinase
Transferase
   PTMPhosphoprotein
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processWnt signaling pathway

Inferred from electronic annotation. Source: UniProtKB-KW

establishment of cell polarity

Inferred from sequence or structural similarity. Source: UniProtKB

establishment or maintenance of epithelial cell apical/basal polarity

Inferred from sequence or structural similarity. Source: UniProtKB

intracellular signal transduction

Inferred from sequence or structural similarity. Source: UniProtKB

neuron migration

Inferred from direct assay Ref.4. Source: UniProtKB

positive regulation of neuron projection development

Inferred from sequence or structural similarity. Source: UniProtKB

protein autophosphorylation

Inferred from direct assay Ref.2. Source: UniProtKB

protein phosphorylation

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of axonogenesis

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of cytoskeleton organization

Inferred from direct assay Ref.2. Source: UniProtKB

   Cellular_componentactin filament

Inferred from sequence or structural similarity. Source: UniProtKB

basal cortex

Inferred from electronic annotation. Source: Ensembl

lateral plasma membrane

Inferred from sequence or structural similarity. Source: UniProtKB

membrane

Inferred from direct assay Ref.4. Source: UniProtKB

microtubule bundle

Inferred from sequence or structural similarity. Source: UniProtKB

nucleus

Inferred from electronic annotation. Source: Ensembl

plasma membrane

Inferred from sequence or structural similarity. Source: UniProtKB

   Molecular_functionATP binding

Inferred from sequence or structural similarity. Source: UniProtKB

lipid binding

Inferred from electronic annotation. Source: UniProtKB-KW

magnesium ion binding

Inferred from sequence or structural similarity. Source: UniProtKB

protein binding

Inferred from physical interaction Ref.4. Source: UniProtKB

protein serine/threonine kinase activity

Inferred from direct assay Ref.4. Source: UniProtKB

tau-protein kinase activity

Inferred from direct assay Ref.2. Source: UniProtKB

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 722722Serine/threonine-protein kinase MARK2
PRO_0000086303

Regions

Domain53 – 304252Protein kinase
Domain323 – 36240UBA
Domain673 – 72250KA1
Nucleotide binding59 – 679ATP By similarity UniProtKB Q9H0K1

Sites

Active site1751Proton acceptor By similarity UniProtKB Q9H0K1
Binding site821ATP By similarity UniProtKB O08678

Amino acid modifications

Modified residue401Phosphoserine By similarity
Modified residue581Phosphothreonine; by autocatalysis Ref.2
Modified residue911Phosphoserine; by CaMK1 Ref.8
Modified residue921Phosphoserine; by CaMK1 Ref.8
Modified residue931Phosphoserine; by CaMK1 Ref.8
Modified residue2081Phosphothreonine; by LKB1 and TAOK1 Ref.2 UniProtKB Q7KZI7
Modified residue2121Phosphoserine; by GSK3-beta Ref.2 Ref.5 Ref.9 UniProtKB O08678
Modified residue2741Phosphoserine; by autocatalysis Ref.2
Modified residue2751Phosphothreonine; by autocatalysis Ref.2
Modified residue2941Phosphothreonine; by CaMK1 Ref.8
Modified residue4091Phosphoserine By similarity
Modified residue4531Phosphoserine By similarity
Modified residue4831Phosphoserine By similarity
Modified residue4901Phosphoserine By similarity
Modified residue5121Phosphoserine By similarity
Modified residue5391Phosphothreonine; by PKC/PRKCZ Ref.7 UniProtKB Q9H0K1
Modified residue5621Phosphoserine By similarity
Modified residue6561Phosphoserine By similarity

Experimental info

Mutagenesis821K → A: Loss of kinase activity. Ref.8
Mutagenesis91 – 933SSS → AAA: Loss of phosphorylation by CaMK1, decrease in kinase activity and ability to promote neurite outgrowth; when associated with A-294. Ref.8
Mutagenesis2081T → A: Abolishes activation of serine/threonine-protein kinase activity and only basal activity remains. Ref.2 Ref.5 Ref.9
Mutagenesis2081T → E: Phosphomimetic mutant that leads to activation but not in presence of GSK3-beta. Ref.2 Ref.5 Ref.9
Mutagenesis2121S → A: Loss of activity; neither activated by TAOK1 nor by STK11/LKB1. Ref.2 Ref.5 Ref.9
Mutagenesis2941T → A: Loss of phosphorylation by CaMK1, decrease in kinase activity and ability to promote neurite outgrowth; when associated with 91-A--A-93. Ref.8
Mutagenesis5391T → A: Abolishes phosphorylation by PKC/PRKCZ. Ref.7

Secondary structure

.................................................... 722
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
O08679 [UniParc].

Last modified July 1, 1997. Version 1.
Checksum: 2CBAFD1C38007ECC

FASTA72280,872
        10         20         30         40         50         60 
MSSARTPLPT LNERDTEQPT LGHLDSKPSS KSNMLRGRNS ATSADEQPHI GNYRLLKTIG 

        70         80         90        100        110        120 
KGNFAKVKLA RHILTGKEVA VKIIDKTQLN SSSLQKLFRE VRIMKVLNHP NIVKLFEVIE 

       130        140        150        160        170        180 
TEKTLYLVME YASGGEVFDY LVAHGRMKEK EARAKFRQIV SAVQYCHQKF IVHRDLKAEN 

       190        200        210        220        230        240 
LLLDADMNIK IADFGFSNEF TFGNKLDTFC GSPPYAAPEL FQGKKYDGPE VDVWSLGVIL 

       250        260        270        280        290        300 
YTLVSGSLPF DGQNLKELRE RVLRGKYRIP FYMSTDCENL LKKFLILNPS KRGTLEQIMK 

       310        320        330        340        350        360 
DRWMNVGHED DELKPYVEPL PDYKDPRRTE LMVSMGYTRE EIQDSLVGQR YNEVMATYLL 

       370        380        390        400        410        420 
LGYKSSELEG DTITLKPRPS ADLTNSSAPS PSHKVQRSVS ANPKQRRSSD QAVPAIPTSN 

       430        440        450        460        470        480 
SYSKKTQSNN AENKRPEEET GRKASSTAKV PASPLPGLDR KKTTPTPSTN SVLSTSTNRS 

       490        500        510        520        530        540 
RNSPLLDRAS LGQASIQNGK DSTAPQRVPV ASPSAHNISS SSGAPDRTNF PRGVSSRSTF 

       550        560        570        580        590        600 
HAGQLRQVRD QQNLPFGVTP ASPSGHSQGR RGASGSIFSK FTSKFVRRNL NEPESKDRVE 

       610        620        630        640        650        660 
TLRPHVVGGG GTDKEKEEFR EAKPRSLRFT WSMKTTSSME PNEMMREIRK VLDANSCQSE 

       670        680        690        700        710        720 
LHERYMLLCV HGTPGHENFV QWEMEVCKLP RLSLNGVRFK RISGTSMAFK NIASKIANEL 


KL 

« Hide

References

[1]"MARK - a novel family of protein kinases that phosphorylate microtubule-associated proteins and trigger microtubule disruption."
Drewes G., Ebneth A., Preuss U., Mandelkow E.-M., Mandelkow E.
Cell 89:297-308(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Strain: Sprague-Dawley.
Tissue: Brain.
[2]"MARKK, a Ste20-like kinase, activates the polarity-inducing kinase MARK/PAR-1."
Timm T., Li X.Y., Biernat J., Jiao J., Mandelkow E., Vandekerckhove J., Mandelkow E.M.
EMBO J. 22:5090-5101(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, ENZYME REGULATION, AUTOPHOSPHORYLATION, PHOSPHORYLATION AT THR-58; THR-208; SER-212; SER-274 AND THR-275, MUTAGENESIS OF THR-208 AND SER-212.
[3]"MARK/PAR1 kinase is a regulator of microtubule-dependent transport in axons."
Mandelkow E.M., Thies E., Trinczek B., Biernat J., Mandelkow E.
J. Cell Biol. 167:99-110(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[4]"Doublecortin microtubule affinity is regulated by a balance of kinase and phosphatase activity at the leading edge of migrating neurons."
Schaar B.T., Kinoshita K., McConnell S.K.
Neuron 41:203-213(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF DCX, SUBCELLULAR LOCATION.
[5]"GSK-3beta directly phosphorylates and activates MARK2/PAR-1."
Kosuga S., Tashiro E., Kajioka T., Ueki M., Shimizu Y., Imoto M.
J. Biol. Chem. 280:42715-42722(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT SER-212, MUTAGENESIS OF THR-208 AND SER-212.
[6]"PAK5 kinase is an inhibitor of MARK/Par-1, which leads to stable microtubules and dynamic actin."
Matenia D., Griesshaber B., Li X.Y., Thiessen A., Johne C., Jiao J., Mandelkow E., Mandelkow E.M.
Mol. Biol. Cell 16:4410-4422(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH PAK7.
[7]"Microtubule affinity-regulating kinase 2 functions downstream of the PAR-3/PAR-6/atypical PKC complex in regulating hippocampal neuronal polarity."
Chen Y.M., Wang Q.J., Hu H.S., Yu P.C., Zhu J., Drewes G., Piwnica-Worms H., Luo Z.G.
Proc. Natl. Acad. Sci. U.S.A. 103:8534-8539(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT THR-539, MUTAGENESIS OF THR-539, FUNCTION.
[8]"A calcium- and calmodulin-dependent kinase Ialpha/microtubule affinity regulating kinase 2 signaling cascade mediates calcium-dependent neurite outgrowth."
Uboha N.V., Flajolet M., Nairn A.C., Picciotto M.R.
J. Neurosci. 27:4413-4423(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT SER-91; SER-92; SER-93 AND THR-294, MUTAGENESIS OF LYS-82; 91-SER--SER-93 AND THR-294.
[9]"Glycogen synthase kinase (GSK) 3beta directly phosphorylates Serine 212 in the regulatory loop and inhibits microtubule affinity-regulating kinase (MARK) 2."
Timm T., Balusamy K., Li X., Biernat J., Mandelkow E., Mandelkow E.M.
J. Biol. Chem. 283:18873-18882(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT SER-212, MUTAGENESIS OF THR-208 AND SER-212.
[10]"Accurate balance of the polarity kinase MARK2/Par-1 is required for proper cortical neuronal migration."
Sapir T., Sapoznik S., Levy T., Finkelshtein D., Shmueli A., Timm T., Mandelkow E.M., Reiner O.
J. Neurosci. 28:5710-5720(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[11]"Structure of the catalytic and ubiquitin-associated domains of the protein kinase MARK/Par-1."
Panneerselvam S., Marx A., Mandelkow E.M., Mandelkow E.
Structure 14:173-183(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 39-364 OF WILD-TYPE AND MUTANT THR-208 AND SER-212, SUBUNIT.
[12]"Structure and function of polarity-inducing kinase family MARK/Par-1 within the branch of AMPK/Snf1-related kinases."
Marx A., Nugoor C., Panneerselvam S., Mandelkow E.
FASEB J. 24:1637-1648(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.79 ANGSTROMS) OF 39-364.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
Z83869 mRNA. Translation: CAB06295.1.
RefSeqNP_067731.1. NM_021699.1.
UniGeneRn.42926.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1Y8GX-ray2.50A/B39-364[»]
1ZMUX-ray2.90A/B39-364[»]
1ZMVX-ray3.10A/B39-364[»]
1ZMWX-ray2.80A/B39-364[»]
2R0IX-ray2.20A/B39-364[»]
2WZJX-ray2.79A/B/C/D/E/F39-364[»]
ProteinModelPortalO08679.
SMRO08679. Positions 49-363, 626-722.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

DIPDIP-29029N.
STRING10116.ENSRNOP00000028765.

PTM databases

PhosphoSiteO08679.

Proteomic databases

PaxDbO08679.
PRIDEO08679.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSRNOT00000028763; ENSRNOP00000028763; ENSRNOG00000021184.
GeneID60328.
KEGGrno:60328.
UCSCRGD:708483. rat.

Organism-specific databases

CTD2011.
RGD708483. Mark2.

Phylogenomic databases

eggNOGCOG0515.
GeneTreeENSGT00730000110535.
HOGENOMHOG000233025.
HOVERGENHBG052453.
KOK08798.
OMAHERYMLL.
OrthoDBEOG79CXXX.

Gene expression databases

GenevestigatorO08679.

Family and domain databases

Gene3D3.30.310.80. 1 hit.
InterProIPR028375. KA1/Ssp2_C.
IPR001772. KA1_dom.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
IPR015940. UBA/transl_elong_EF1B_N_euk.
[Graphical view]
PfamPF02149. KA1. 1 hit.
PF00069. Pkinase. 1 hit.
[Graphical view]
SMARTSM00220. S_TKc. 1 hit.
SM00165. UBA. 1 hit.
[Graphical view]
SUPFAMSSF103243. SSF103243. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEPS50032. 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]
ProtoNetSearch...

Other

EvolutionaryTraceO08679.
NextBio611957.

Entry information

Entry nameMARK2_RAT
AccessionPrimary (citable) accession number: O08679
Entry history
Integrated into UniProtKB/Swiss-Prot: April 12, 2005
Last sequence update: July 1, 1997
Last modified: July 9, 2014
This is version 117 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references