O08679 (MARK2_RAT) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Rattus norvegicus (Rat) [Reference proteome]

Taxonomic identifier

10116 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus

Protein attributes

Sequence length	722 AA.
Sequence status	Complete.
Protein existence	Evidence 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 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. 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 process	Differentiation Wnt signaling pathway
Cellular component	Cell membrane Cytoplasm Membrane
Ligand	ATP-binding Lipid-binding Magnesium Metal-binding Nucleotide-binding
Molecular function	Developmental protein Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	Wnt receptor 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 protein kinase cascade 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 regulation of axonogenesis Inferred from sequence or structural similarity. Source: UniProtKB regulation of cytoskeleton organization Inferred from direct assay Ref.2. Source: UniProtKB response to oxidative stress Inferred from electronic annotation. Source: Compara
Cellular_component	basal cortex Inferred from electronic annotation. Source: Compara membrane Inferred from direct assay Ref.4. Source: UniProtKB nucleus Inferred from electronic annotation. Source: Compara plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	ATP 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 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 key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 722

722

Serine/threonine-protein kinase MARK2

PRO_0000086303

Regions

Domain

53 – 304

252

Protein kinase

Domain

323 – 362

40

UBA

Domain

673 – 722

50

KA1

Nucleotide binding

59 – 67

9

ATP By similarity UniProtKB Q9H0K1

Sites

Active site

175

1

Proton acceptor By similarity UniProtKB Q9H0K1

Binding site

82

1

ATP By similarity UniProtKB O08678

Amino acid modifications

Modified residue

40

1

Phosphoserine By similarity

Modified residue

58

1

Phosphothreonine; by autocatalysis Ref.2

Modified residue

91

1

Phosphoserine; by CaMK1 Ref.8

Modified residue

92

1

Phosphoserine; by CaMK1 Ref.8

Modified residue

93

1

Phosphoserine; by CaMK1 Ref.8

Modified residue

208

1

Phosphothreonine; by LKB1 and TAOK1 Ref.2 UniProtKB Q7KZI7

Modified residue

212

1

Phosphoserine; by GSK3-beta Ref.2 Ref.5 Ref.9 UniProtKB O08678

Modified residue

274

1

Phosphoserine; by autocatalysis Ref.2

Modified residue

275

1

Phosphothreonine; by autocatalysis Ref.2

Modified residue

294

1

Phosphothreonine; by CaMK1 Ref.8

Modified residue

409

1

Phosphoserine By similarity

Modified residue

453

1

Phosphoserine By similarity

Modified residue

483

1

Phosphoserine By similarity

Modified residue

490

1

Phosphoserine By similarity

Modified residue

512

1

Phosphoserine By similarity

Modified residue

514

1

Phosphoserine By similarity

Modified residue

538

1

Phosphoserine By similarity

Modified residue

539

1

Phosphothreonine; by PKC/PRKCZ Ref.7 UniProtKB Q9H0K1

Modified residue

562

1

Phosphoserine

Modified residue

656

1

Phosphoserine By similarity

Experimental info

Mutagenesis

82

1

K → A: Loss of kinase activity. Ref.8

Mutagenesis

91 – 93

3

SSS → AAA: Loss of phosphorylation by CaMK1, decrease in kinase activity and ability to promote neurite outgrowth; when associated with A-294. Ref.8

Mutagenesis

208

1

T → A: Abolishes activation of serine/threonine-protein kinase activity and only basal activity remains. Ref.2 Ref.5 Ref.9

Mutagenesis

208

1

T → E: Phosphomimetic mutant that leads to activation but not in presence of GSK3-beta. Ref.2 Ref.5 Ref.9

Mutagenesis

212

1

S → A: Loss of activity; neither activated by TAOK1 nor by STK11/LKB1. Ref.2 Ref.5 Ref.9

Mutagenesis

294

1

T → 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

Mutagenesis

539

1

T → A: Abolishes phosphorylation by PKC/PRKCZ. Ref.7

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

722

Helix Strand Turn

Details...

Beta strand

53 – 61

9

Beta strand

63 – 72

10

Turn

73 – 75

3

Beta strand

78 – 85

8

Helix

86 – 88

3

Helix

91 – 106

16

Beta strand

115 – 120

6

Beta strand

122 – 130

9

Helix

137 – 144

8

Helix

149 – 168

20

Helix

178 – 180

3

Beta strand

181 – 183

3

Beta strand

189 – 191

3

Beta strand

194 – 196

3

Beta strand

202 – 205

4

Turn

208 – 211

4

Helix

213 – 215

3

Helix

219 – 222

4

Helix

229 – 245

17

Helix

255 – 264

10

Helix

275 – 284

10

Helix

289 – 291

3

Helix

295 – 298

4

Helix

302 – 305

4

Helix

326 – 334

9

Helix

339 – 347

9

Helix

353 – 361

9

Sequences

	Sequence		Length	Mass (Da)
	O08679 [UniParc]. Last modified July 1, 1997. Version 1. Checksum: 2CBAFD1C38007ECC	FASTA	722	80,872
	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

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.

IPI

IPI00194773.

RefSeq

NP_067731.1. NM_021699.1.

UniGene

Rn.42926.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1Y8G	X-ray	2.50	A/B	39-364	[»]
1ZMU	X-ray	2.90	A/B	39-364	[»]
1ZMV	X-ray	3.10	A/B	39-364	[»]
1ZMW	X-ray	2.80	A/B	39-364	[»]
2R0I	X-ray	2.20	A/B	39-364	[»]
2WZJ	X-ray	2.79	A/B/C/D/E/F	39-364	[»]

ProteinModelPortal

O08679.

SMR

O08679. Positions 49-363, 626-722.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-29029N.

PTM databases

PhosphoSite

O08679.

Proteomic databases

PaxDb

O08679.

PRIDE

O08679.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENSRNOT00000028763; ENSRNOP00000028763; ENSRNOG00000021184.

GeneID

60328.

KEGG

rno:60328.

UCSC

RGD:708483. rat.

Organism-specific databases

CTD

2011.

RGD

708483. Mark2.

Phylogenomic databases

eggNOG

COG0515.

GeneTree

ENSGT00690000101885.

HOGENOM

HOG000233025.

HOVERGEN

HBG052453.

KO

K08798.

Gene expression databases

ArrayExpress

O08679.

Genevestigator

O08679.

GermOnline

ENSRNOG00000021184. Rattus norvegicus.

Family and domain databases

InterPro

IPR001772. KA1_dom.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_cat_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]

Pfam

PF02149. KA1. 1 hit.
PF00069. Pkinase. 1 hit.
[Graphical view]

SMART

SM00220. S_TKc. 1 hit.
SM00165. UBA. 1 hit.
[Graphical view]

SUPFAM

SSF103243. Kinase-assoc_KA1. 1 hit.
SSF56112. Kinase_like. 1 hit.

PROSITE

PS50032. 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]

ProtoNet

Search...

Other

EvolutionaryTrace

O08679.

NextBio

611957.

Entry information

Entry name

MARK2_RAT

Accession

Primary (citable) accession number: O08679

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 12, 2005
Last sequence update:	July 1, 1997
Last modified:	April 3, 2013
This is version 105 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program