P63086 (MK01_RAT) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Mitogen-activated protein kinase 1
Short name=MAP kinase 1
Short name=MAPK 1
EC=2.7.11.24

Alternative name(s):
ERT1
Extracellular signal-regulated kinase 2
Short name=ERK-2
MAP kinase isoform p42
Short name=p42-MAPK
Mitogen-activated protein kinase 2
Short name=MAP kinase 2
Short name=MAPK 2

Gene names

Name:	Mapk1
Synonyms:	Erk2, Mapk, Prkm1

Organism

Rattus norvegicus (Rat)

Taxonomic identifier

10116 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus

Protein attributes

Sequence length	358 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK1/ERK2 and MAPK3/ERK1 are the 2 MAPKs which play an important role in the MAPK/ERK cascade. They participate also in a signaling cascade initiated by activated KIT and KITLG/SCF. Depending on the cellular context, the MAPK/ERK cascade mediates diverse biological functions such as cell growth, adhesion, survival and differentiation through the regulation of transcription, translation, cytoskeletal rearrangements. The the MAPK/ERK cascade plays also a role in initiation and regulation of meiosis, mitosis, and postmitotic functions in differentiated cells by phosphorylating a number of transcription factors. About 160 substrates have already been discovered for ERKs. Many of these substrates are localized in the nucleus, and seem to participate in the regulation of transcription upon stimulation. However, other substrates are found in the cytosol as well as in other cellular organelles, and those are responsible for processes such as translation, mitosis and apoptosis. Moreover, the MAPK/ERK cascade is also involved in the regulation of the endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC); as well as in the fragmentation of the Golgi apparatus during mitosis. The substrates include transcription factors (such as ATF2, BCL6, ELK1, ERF, FOS, HSF4 or SPZ1), cytoskeletal elements (such as CANX, CTTN, GJA1, MAP2, MAPT, PXN, SORBS3 or STMN1), regulators of apoptosis (such as BAD, BTG2, CASP9, DAPK1, IER3, MCL1 or PPARG), regulators of translation (such as EIF4EBP1) and a variety of other signaling-related molecules (like ARHGEF2, FRS2 or GRB10). Protein kinases (such as RAF1, RPS6KA1/RSK1, RPS6KA3/RSK2, RPS6KA2/RSK3, RPS6KA6/RSK4, SYK, MKNK1/MNK1, MKNK2/MNK2, RPS6KA5/MSK1, RPS6KA4/MSK2, MAPKAPK3 or MAPKAPK5) and phosphatases (such as DUSP1, DUSP4, DUSP6 or DUSP16) are other substrates which enable the propagation the MAPK/ERK signal to additionnal cytosolic and nuclear targets, thereby extending the specificity of the cascade. Acts as a transcriptional repressor. Binds to a [GC]AAA[GC] consensus sequence. Repress the expression of interferon gamma-induced genes. Seems to bind to the promoter of CCL5, DMP1, IFIH1, IFITM1, IRF7, IRF9, LAMP3, OAS1, OAS2, OAS3 and STAT1. Transcriptional activity is independent of kinase activity By similarity.
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Cofactor	Magnesium By similarity.
Enzyme regulation	Phosphorylated by MAP2K1/MEK1 and MAP2K2/MEK2 on Thr-183 and Tyr-185 in response to external stimuli like insulin or NGF. Both phosphorylations are required for activity. This phosphorylation causes dramatic conformational changes, which enable full activation and interaction of MAPK1/ERK2 with its substrates. Phosphorylation on Ser-27 by SGK1 results in its activation by enhancing its interaction with MAP2K1/MEK1 and MAP2K2/MEK2. Dephospphorylated and inactivated by DUSP3, DUSP6 and DUSP9. Inactivated by pyrimidylpyrrole inhibitors.
Subunit structure	Binds both upstream activators and downstream substrates in multimolecular complexes. Interacts with ADAM15, ARHGEF2, ARRB2, DAPK1 (via death domain), HSF4, IER3, IPO7, MKNK2, DUSP6, MORG1, NISCH, PEA15, SGK1, and isoform 1 of NEK2 By similarity. Interacts (phosphorylated form) with CAV2 ('Tyr-19'-phosphorylated form); the interaction, promoted by insulin, leads to nuclear location and MAPK1 activation By similarity. MKNK2 isoform 1 binding prevents from dephosphorylation and inactivation By similarity. Ref.6 Ref.8 Ref.9 Ref.17
Subcellular location	Nucleus By similarity. Cytoplasm › cytoskeleton › centrosome By similarity. Cytoplasm By similarity. Note: PEA15-binding and phosphorylated DAPK1 promote its cytoplasmic retention By similarity. Phosphorylation at Ser-244 and Ser-246 as well as autophosphorylation at Thr-188 promote nuclear localization By similarity.
Tissue specificity	Highest levels within the nervous system, expressed in different tissues, mostly in muscle, thymus and heart.
Developmental stage	Increased expression during development.
Domain	The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.
Post-translational modification	Dually phosphorylated on Thr-183 and Tyr-185, which activates the enzyme. Phosphorylated upon FLT3 and KIT signaling. Ligand-activated ALK induces tyrosine phosphorylation By similarity. Dephosphorylated by PTPRJ at Tyr-185 By similarity. Autophosphorylated on threonine and tyrosine residues in vitro, which correlates with a slow and low level of activation. Phosphorylation on Ser-27 by SGK1 results in its activation by enhancing its interaction with MAP2K1/MEK1 and MAP2K2/MEK2 By similarity. Ref.4 Ref.5 Ref.7
Sequence similarities	Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily. Contains 1 protein kinase domain.

Ontologies

Keywords
Biological process	Apoptosis Cell cycle
Cellular component	Cytoplasm Cytoskeleton Nucleus
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological process	MAPK import into nucleus Inferred from direct assay. Source: RGD cell cycle Inferred from electronic annotation. Source: UniProtKB-KW positive regulation of cell migration Inferred from expression pattern. Source: RGD positive regulation of cell proliferation Inferred from expression pattern. Source: RGD positive regulation of transcription, DNA-dependent Inferred from expression pattern. Source: RGD positive regulation of translation Inferred from mutant phenotype. Source: RGD response to estrogen stimulus Inferred from direct assay. Source: RGD response to toxin Inferred from direct assay. Source: RGD sensory perception of pain Inferred from mutant phenotype. Source: UniProtKB
Cellular component	axon part Inferred from direct assay. Source: RGD cytosol Inferred from direct assay. Source: RGD dendrite cytoplasm Inferred from direct assay. Source: RGD insoluble fraction Inferred from direct assay. Source: RGD microtubule organizing center Inferred from electronic annotation. Source: UniProtKB-SubCell nucleoplasm Inferred from direct assay. Source: UniProtKB perikaryon Inferred from direct assay. Source: RGD protein complex Inferred from direct assay. Source: RGD soluble fraction Inferred from direct assay. Source: RGD
Molecular function	ATP binding Inferred from direct assay. Source: RGD MAP kinase activity Inferred from direct assay. Source: UniProtKB mitogen-activated protein kinase kinase kinase binding Inferred from physical interaction. Source: RGD transcription factor binding Inferred from physical interaction. Source: RGD
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

1

1

Removed Ref.2

Chain

2 – 358

357

Mitogen-activated protein kinase 1

PRO_0000186249

Regions

Domain

23 – 311

289

Protein kinase

Nucleotide binding

29 – 37

9

ATP

Region

103 – 109

7

Inhibitor-binding

Motif

183 – 185

3

TXY

Compositional bias

2 – 7

6

Poly-Ala

Sites

Active site

147

1

Proton acceptor

Binding site

52

1

ATP

Binding site

106

1

Inhibitor; via amide nitrogen and carbonyl oxygen

Binding site

164

1

Inhibitor

Amino acid modifications

Modified residue

2

1

N-acetylalanine Ref.2

Modified residue

27

1

Phosphoserine; by SGK1 By similarity

Modified residue

61

1

Phosphothreonine By similarity

Modified residue

179

1

Phosphothreonine By similarity

Modified residue

183

1

Phosphothreonine; by MAP2K1 and MAP2K2 By similarity

Modified residue

185

1

Phosphotyrosine; by MAP2K1 and MAP2K2 By similarity

Modified residue

188

1

Phosphothreonine; by autocatalysis Ref.7

Modified residue

200

1

Phosphoserine By similarity

Modified residue

244

1

Phosphoserine By similarity

Modified residue

246

1

Phosphoserine By similarity

Modified residue

282

1

Phosphoserine By similarity

Secondary structure

1

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358

Helix Strand Turn

Details...

Helix

20 – 22

3

Beta strand

23 – 31

9

Beta strand

36 – 42

7

Turn

43 – 46

4

Beta strand

47 – 54

8

Helix

60 – 75

16

Beta strand

84 – 88

5

Turn

93 – 95

3

Beta strand

99 – 104

6

Beta strand

107 – 109

3

Helix

110 – 114

5

Helix

121 – 140

20

Helix

150 – 152

3

Beta strand

153 – 155

3

Beta strand

161 – 163

3

Helix

174 – 176

3

Helix

189 – 191

3

Helix

194 – 196

3

Turn

197 – 199

3

Helix

206 – 221

16

Helix

231 – 242

12

Helix

247 – 250

4

Helix

256 – 263

8

Helix

273 – 276

4

Helix

282 – 291

10

Turn

296 – 298

3

Helix

302 – 306

5

Helix

309 – 311

3

Turn

312 – 314

3

Helix

317 – 319

3

Helix

338 – 349

12

Sequences

	Sequence		Length	Mass (Da)
	P63086 [UniParc]. Last modified January 23, 2007. Version 3. Checksum: 3BBCF22471EDBA0B	FASTA	358	41,276
	10 20 30 40 50 60 MAAAAAAGPE MVRGQVFDVG PRYTNLSYIG EGAYGMVCSA YDNLNKVRVA IKKISPFEHQ 70 80 90 100 110 120 TYCQRTLREI KILLRFRHEN IIGINDIIRA PTIEQMKDVY IVQDLMETDL YKLLKTQHLS 130 140 150 160 170 180 NDHICYFLYQ ILRGLKYIHS ANVLHRDLKP SNLLLNTTCD LKICDFGLAR VADPDHDHTG 190 200 210 220 230 240 FLTEYVATRW YRAPEIMLNS KGYTKSIDIW SVGCILAEML SNRPIFPGKH YLDQLNHILG 250 260 270 280 290 300 ILGSPSQEDL NCIINLKARN YLLSLPHKNK VPWNRLFPNA DSKALDLLDK MLTFNPHKRI 310 320 330 340 350 EVEQALAHPY LEQYYDPSDE PIAEAPFKFD MELDDLPKEK LKELIFEETA RFQPGYRS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"ERKs: a family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF." Boulton T.G., Nye S.H., Robbins D.J., Ip N.Y., Radziejewska E., Morgenbesser S.D., DePinho R.A., Panayotatos N., Cobb M.H., Yancopoulos G.D. Cell 65:663-675(1991) [PubMed: 2032290] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Strain: Sprague-Dawley. Tissue: Brain.
[2]	Bienvenut W.V., von Kriegsheim A.F., Kolch W. Submitted (AUG-2006) to UniProtKB Cited for: PROTEIN SEQUENCE OF 2-13; 69-75; 137-170; 193-201 AND 341-351, CLEAVAGE OF INITIATOR METHIONINE, ACETYLATION AT ALA-2, MASS SPECTROMETRY. Tissue: Pheochromocytoma.
[3]	Lubec G., Kang S.U. Submitted (JUL-2007) to UniProtKB Cited for: PROTEIN SEQUENCE OF 163-170, MASS SPECTROMETRY. Strain: Sprague-Dawley. Tissue: Brain.
[4]	"Microtubule-associated protein 2 kinases, ERK1 and ERK2, undergo autophosphorylation on both tyrosine and threonine residues: implications for their mechanism of activation." Seger R., Ahn N.G., Boulton T.G., Yancopoulos G.D., Panayotatos N., Radziejewska E., Ericsson L., Bratlien R.L., Cobb M.H., Krebs E.G. Proc. Natl. Acad. Sci. U.S.A. 88:6142-6146(1991) [PubMed: 1712480] [Abstract] Cited for: AUTOPHOSPHORYLATION.
[5]	"PHAS-I as a link between mitogen-activated protein kinase and translation initiation." Lin T.-A., Kong X., Haystead T.A.J., Pause A., Belsham G.J., Sonenberg N., Lawrence J.C. Jr. Science 266:653-656(1994) [PubMed: 7939721] [Abstract] Cited for: PHOSPHORYLATION OF EIF4EBP1.
[6]	"Activation and targeting of extracellular signal-regulated kinases by beta-arrestin scaffolds." Luttrell L.M., Roudabush F.L., Choy E.W., Miller W.E., Field M.E., Pierce K.L., Lefkowitz R.J. Proc. Natl. Acad. Sci. U.S.A. 98:2449-2454(2001) [PubMed: 11226259] [Abstract] Cited for: INTERACTION WITH ARRB2.
[7]	"Quantitative phosphoproteomics of vasopressin-sensitive renal cells: regulation of aquaporin-2 phosphorylation at two sites." Hoffert J.D., Pisitkun T., Wang G., Shen R.-F., Knepper M.A. Proc. Natl. Acad. Sci. U.S.A. 103:7159-7164(2006) [PubMed: 16641100] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-183; TYR-185 AND THR-188, MASS SPECTROMETRY. Tissue: Renal collecting duct.
[8]	"Identification of pY19-caveolin-2 as a positive regulator of insulin-stimulated actin cytoskeleton-dependent mitogenesis." Kwon H., Jeong K., Pak Y. J. Cell. Mol. Med. 13:1549-1564(2009) [PubMed: 19778377] [Abstract] Cited for: INTERACTION WITH CAV2.
[9]	"Caveolin-2 regulation of STAT3 transcriptional activation in response to insulin." Kwon H., Jeong K., Hwang E.M., Park J.-Y., Hong S.-G., Choi W.-S., Pak Y. Biochim. Biophys. Acta 1793:1325-1333(2009) [PubMed: 19427337] [Abstract] Cited for: INTERACTION WITH CAV2.
[10]	"The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions." Yoon S., Seger R. Growth Factors 24:21-44(2006) [PubMed: 16393692] [Abstract] Cited for: REVIEW ON FUNCTION.
[11]	"The ERK signaling cascade--views from different subcellular compartments." Yao Z., Seger R. BioFactors 35:407-416(2009) [PubMed: 19565474] [Abstract] Cited for: REVIEW ON FUNCTION, REVIEW ON SUBCELLULAR LOCATION.
[12]	"The ERK cascade: distinct functions within various subcellular organelles." Wortzel I., Seger R. Genes Cancer 2:195-209(2011) [PubMed: 21779493] [Abstract] Cited for: REVIEW ON ENZYME REGULATION, REVIEW ON FUNCTION.
[13]	"Atomic structure of the MAP kinase ERK2 at 2.3-A resolution." Zhang F., Strand A., Robbins D., Cobb M.H., Goldsmith E.J. Nature 367:704-710(1994) [PubMed: 8107865] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS).
[14]	"Mutation of position 52 in ERK2 creates a nonproductive binding mode for adenosine 5'-triphosphate." Robinson M.J., Harkins P.C., Zhang J., Baer R., Haycock J.W., Cobb M.H., Goldsmith E.J. Biochemistry 35:5641-5646(1996) [PubMed: 8639522] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.80 ANGSTROMS) IN COMPLEX WITH ATP.
[15]	"Activation mechanism of the MAP kinase ERK2 by dual phosphorylation." Canagarajah B.J., Khokhlatchev A., Cobb M.H., Goldsmith E.J. Cell 90:859-869(1997) [PubMed: 9298898] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS).
[16]	"Structural basis of inhibitor selectivity in MAP kinases." Wang Z., Canagarajah B.J., Boehm J.C., Kassisa S., Cobb M.H., Young P.R., Abdel-Meguid S., Adams J.L., Goldsmith E.J. Structure 6:1117-1128(1998) [PubMed: 9753691] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) IN COMPLEX WITH INHIBITOR.
[17]	"Structural basis of docking interactions between ERK2 and MAP kinase phosphatase 3." Liu S., Sun J.P., Zhou B., Zhang Z.Y. Proc. Natl. Acad. Sci. U.S.A. 103:5326-5331(2006) [PubMed: 16567630] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) OF 2-357, INTERACTION WITH DUSP6.
[18]	"Docking interactions induce exposure of activation loop in the MAP kinase ERK2." Zhou T., Sun L., Humphreys J., Goldsmith E.J. Structure 14:1011-1019(2006) [PubMed: 16765894] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) OF 2-357.
[19]	"Molecular modeling and crystal structure of ERK2-hypothemycin complexes." Rastelli G., Rosenfeld R., Reid R., Santi D.V. J. Struct. Biol. 164:18-23(2008) [PubMed: 18571434] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) OF 2-358 IN COMPLEX WITH INHIBITOR.
[20]	"Identification of a key element for hydrogen-bonding patterns between protein kinases and their inhibitors." Katayama N., Orita M., Yamaguchi T., Hisamichi H., Kuromitsu S., Kurihara H., Sakashita H., Matsumoto Y., Fujita S., Niimi T. Proteins 73:795-801(2008) [PubMed: 18767165] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.41 ANGSTROMS) IN COMPLEX WITH INHIBITOR.
[21]	"Phosphorylation of DCC by ERK2 is facilitated by direct docking of the receptor P1 domain to the kinase." Ma W., Shang Y., Wei Z., Wen W., Wang W., Zhang M. Structure 18:1502-1511(2010) [PubMed: 21070949] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS).
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

M64300 mRNA. Translation: AAA41124.1.

IPI

IPI00199688.

PIR

A40033.

RefSeq

NP_446294.1. NM_053842.1.

UniGene

Rn.34914.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1ERK	X-ray	2.30	A	1-358	[»]
1GOL	X-ray	2.80	A	1-358	[»]
2ERK	X-ray	2.40	A	1-358	[»]
2FYS	X-ray	2.50	A/B	2-357	[»]
2GPH	X-ray	1.90	A	2-357	[»]
2Z7L	X-ray	2.41	A	1-358	[»]
3C9W	X-ray	2.50	A/B	2-358	[»]
3ERK	X-ray	2.10	A	1-358	[»]
3O71	X-ray	1.95	A	1-358	[»]
3QYW	X-ray	1.50	A	1-358	[»]
3QYZ	X-ray	1.46	A	1-358	[»]
3R63	X-ray	1.70	A	1-358	[»]
4ERK	X-ray	2.20	A	1-358	[»]

ProteinModelPortal

P63086.

SMR

P63086. Positions 6-355.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-29117N.

IntAct

P63086. 2 interactions.

MINT

MINT-100037.

STRING

P63086.

PTM databases

PhosphoSite

P63086.

2D gel databases

World-2DPAGE

0004:P63086.

Proteomic databases

PRIDE

P63086.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

GeneID

116590.

KEGG

rno:116590.

Organism-specific databases

CTD

5594.

RGD

70500. Mapk1.

Phylogenomic databases

eggNOG

roNOG04134.

GeneTree

ENSGT00550000074298.

HOVERGEN

HBG014652.

InParanoid

P63086.

OrthoDB

EOG45HRXM.

PhylomeDB

P63086.

Enzyme and pathway databases

BRENDA

2.7.11.24. 5301.

Reactome

REACT_109781. Immune System.
REACT_111984. Signal Transduction.
REACT_112697. Developmental Biology.

Gene expression databases

ArrayExpress

P63086.

Genevestigator

P63086.

GermOnline

ENSRNOG00000001849. Rattus norvegicus.

Family and domain databases

InterPro

IPR008349. Erk_1_2_MAPK.
IPR011009. Kinase-like_dom.
IPR003527. MAP_kinase_CS.
IPR000719. Prot_kinase_cat_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR017442. Se/Thr_kinase-like_dom.
IPR008271. Ser/Thr_kinase_AS.
IPR002290. Ser/Thr_kinase_dom.
[Graphical view]

KO

K04371.

Pfam

PF00069. Pkinase. 1 hit.
[Graphical view]

PRINTS

PR01770. ERK1ERK2MAPK.

SMART

SM00220. S_TKc. 1 hit.
[Graphical view]

SUPFAM

SSF56112. Kinase_like. 1 hit.

PROSITE

PS01351. MAPK. 1 hit.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

NextBio

619269.

Entry information

Entry name

MK01_RAT

Accession

Primary (citable) accession number: P63086
Secondary accession number(s): P27703

Entry history

Integrated into UniProtKB/Swiss-Prot:	September 13, 2004
Last sequence update:	January 23, 2007
Last modified:	January 25, 2012
This is version 97 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program