P21708 (MK03_RAT) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Mitogen-activated protein kinase 3
Short name=MAP kinase 3
Short name=MAPK 3
EC=2.7.11.24

Alternative name(s):
ERT2
Extracellular signal-regulated kinase 1
Short name=ERK-1
Insulin-stimulated MAP2 kinase
MAP kinase isoform p44
Short name=p44-MAPK
MNK1
Microtubule-associated protein 2 kinase
p44-ERK1

Gene names

Name:	Mapk3
Synonyms:	Erk1, Prkm3

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	380 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 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 additional cytosolic and nuclear targets, thereby extending the specificity of the cascade.
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Cofactor	Magnesium By similarity.
Enzyme regulation	Phosphorylated by MAP2K1/MEK1 and MAP2K2/MEK2 on Thr-203 and Tyr-205 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. Dephosphorylated and inactivated by DUSP3, DUSP6 and DUSP9.
Subunit structure	Binds both upstream activators and downstream substrates in multimolecular complexes. Found in a complex with at least BRAF, HRAS1, MAP2K1/MEK1, MAPK3 and RGS14. Interacts with ADAM15, ARRB2, CANX, DAPK1 (via death domain), HSF4, IER3, MAP2K1/MEK1, MORG1, NISCH, PEA15, SGK1 and MKNK2 By similarity. MKNK2 isoform 1 binding prevents from dephosphorylation and inactivation. Interacts with TPR By similarity. Ref.12
Subcellular location	Cytoplasm By similarity. Nucleus. Note: Autophosphorylation at Thr-207 promotes nuclear localization By similarity. PEA15-binding redirects the biological outcome of MAPK3 kinase-signaling by sequestering MAPK3 into the cytoplasm By similarity. Isoform 2: Nucleus.
Tissue specificity	Highest levels within the nervous system, expressed in different tissues, mostly in intestine, placenta and lung.
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	Phosphorylated upon FLT3 and KIT signaling. Ligand-activated ALK induces tyrosine phosphorylation By similarity. Dephosphorylated by PTPRJ at Tyr-205 By similarity. Dually phosphorylated on Thr-203 and Tyr-205, which activates the enzyme. Ref.3 Ref.9 Ref.10
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 Nucleus
Coding sequence diversity	Alternative splicing
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Acetylation Phosphoprotein
Technical term	Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	MAPK import into nucleus Inferred from direct assay PubMed 12097495. Source: RGD apoptotic process Inferred from electronic annotation. Source: UniProtKB-KW arachidonic acid metabolic process Inferred from expression pattern PubMed 15027896. Source: RGD caveolin-mediated endocytosis Traceable author statement Ref.14. Source: UniProtKB cell cycle Inferred from electronic annotation. Source: UniProtKB-KW positive regulation of transcription, DNA-dependent Inferred from expression pattern PubMed 12097495. Source: RGD positive regulation of translation Inferred from mutant phenotype PubMed 15027896. Source: RGD protein complex assembly Inferred from mutant phenotype PubMed 7889942. Source: UniProtKB regulation of Golgi inheritance Traceable author statement Ref.14. Source: UniProtKB regulation of cytoskeleton organization Traceable author statement Ref.14. Source: UniProtKB regulation of early endosome to late endosome transport Traceable author statement Ref.14. Source: UniProtKB regulation of stress-activated MAPK cascade Traceable author statement Ref.14. Source: UniProtKB response to epidermal growth factor stimulus Inferred from sequence or structural similarity. Source: UniProtKB response to toxin Inferred from direct assay PubMed 17651772. Source: RGD
Cellular_component	Golgi apparatus Traceable author statement Ref.14. Source: UniProtKB caveola Traceable author statement Ref.14. Source: UniProtKB cytoskeleton Traceable author statement Ref.14. Source: UniProtKB cytosol Traceable author statement Ref.14. Source: UniProtKB early endosome Traceable author statement Ref.14. Source: UniProtKB focal adhesion Traceable author statement Ref.14. Source: UniProtKB late endosome Traceable author statement Ref.14. Source: UniProtKB mitochondrion Traceable author statement Ref.14. Source: UniProtKB nucleoplasm Inferred from direct assay PubMed 7889942. Source: UniProtKB protein complex Inferred from direct assay PubMed 15781236. Source: RGD
Molecular_function	ATP binding Inferred from direct assay PubMed 15027896. Source: RGD MAP kinase activity Inferred from direct assay PubMed 7889942. Source: UniProtKB
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P21708-1)

Also known as: A;

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.

Isoform 2 (identifier: P21708-2)

Also known as: B;

The sequence of this isoform differs from the canonical sequence as follows:
     340-340: E → EVSRPPAAGRGISVPSVRPVPYCLCPQ

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Initiator methionine	1	1	Removed Ref.3
	Chain	2 – 380	379	Mitogen-activated protein kinase 3		PRO_0000186253
Regions
	Domain	43 – 331	289	Protein kinase
	Nucleotide binding	49 – 57	9	ATP By similarity
	Motif	203 – 205	3	TXY
Sites
	Active site	167	1	Proton acceptor By similarity
	Binding site	72	1	ATP By similarity
Amino acid modifications
	Modified residue	2	1	N-acetylalanine Ref.3
	Modified residue	171	1	Phosphoserine By similarity
	Modified residue	199	1	Phosphothreonine By similarity
	Modified residue	203	1	Phosphothreonine; by MAP2K1 and MAP2K2 Ref.3 Ref.11
	Modified residue	205	1	Phosphotyrosine; by MAP2K1 and MAP2K2 Ref.3 Ref.11
	Modified residue	208	1	Phosphothreonine; by autocatalysis By similarity
Natural variations
	Alternative sequence	340	1	E → EVSRPPAAGRGISVPSVRPV PYCLCPQ in isoform 2.		VSP_004830
Experimental info
	Sequence conflict	95	1	R → G in AAA11604. Ref.1
	Sequence conflict	95	1	R → G in CAA46318. Ref.1
	Sequence conflict	95	1	R → G in AAA63486. Ref.4
	Sequence conflict	95	1	R → G in AAA20009. Ref.7

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (A) [UniParc]. Last modified January 23, 2007. Version 5. Checksum: 49C4EA95B627237F	FASTA	380	43,081
	10 20 30 40 50 60 MAAAAAAPGG GGGEPRGTAG VVPVVPGEVE VVKGQPFDVG PRYTQLQYIG EGAYGMVSSA 70 80 90 100 110 120 YDHVRKTRVA IKKISPFEHQ TYCQRTLREI QILLRFRHEN VIGIRDILRA PTLEAMRDVY 130 140 150 160 170 180 IVQDLMETDL YKLLKSQQLS NDHICYFLYQ ILRGLKYIHS ANVLHRDLKP SNLLINTTCD 190 200 210 220 230 240 LKICDFGLAR IADPEHDHTG FLTEYVATRW YRAPEIMLNS KGYTKSIDIW SVGCILAEML 250 260 270 280 290 300 SNRPIFPGKH YLDQLNHILG ILGSPSQEDL NCIINMKARN YLQSLPSKTK VAWAKLFPKS 310 320 330 340 350 360 DSKALDLLDR MLTFNPNKRI TVEEALAHPY LEQYYDPTDE PVAEEPFTFD MELDDLPKER 370 380 LKELIFQETA RFQPGAPEAP
	Isoform 2 (B) [UniParc]. Checksum: 2F40B2DFA5A116B0	FASTA	406	45,770
	10 20 30 40 50 60 MAAAAAAPGG GGGEPRGTAG VVPVVPGEVE VVKGQPFDVG PRYTQLQYIG EGAYGMVSSA 70 80 90 100 110 120 YDHVRKTRVA IKKISPFEHQ TYCQRTLREI QILLRFRHEN VIGIRDILRA PTLEAMRDVY 130 140 150 160 170 180 IVQDLMETDL YKLLKSQQLS NDHICYFLYQ ILRGLKYIHS ANVLHRDLKP SNLLINTTCD 190 200 210 220 230 240 LKICDFGLAR IADPEHDHTG FLTEYVATRW YRAPEIMLNS KGYTKSIDIW SVGCILAEML 250 260 270 280 290 300 SNRPIFPGKH YLDQLNHILG ILGSPSQEDL NCIINMKARN YLQSLPSKTK VAWAKLFPKS 310 320 330 340 350 360 DSKALDLLDR MLTFNPNKRI TVEEALAHPY LEQYYDPTDE VSRPPAAGRG ISVPSVRPVP 370 380 390 400 YCLCPQPVAE EPFTFDMELD DLPKERLKEL IFQETARFQP GAPEAP

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Sequence of a rat cDNA encoding the ERK1-MAP kinase." Marquardt B., Stabel S. Gene 120:297-299(1992) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Strain: Sprague-Dawley. Tissue: Brain.
[2]	"ERK1b, a 46-kDa ERK isoform that is differentially regulated by MEK." Yung Y., Yao Z., Hanoch T., Seger R. J. Biol. Chem. 275:15799-15808(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
[3]	Bienvenut W.V., von Kriegsheim A.F., Kolch W. Submitted (AUG-2006) to UniProtKB Cited for: PROTEIN SEQUENCE OF 2-65; 96-132; 157-209; 213-221; 280-357 AND 361-380 (ISOFORM 2), CLEAVAGE OF INITIATOR METHIONINE, ACETYLATION AT ALA-2, PHOSPHORYLATION AT THR-203 AND TYR-205, MASS SPECTROMETRY. Tissue: Pheochromocytoma.
[4]	Maisonpierre P.C., le Beau M.M., Espinosa R. III, Ip N.Y., Belluscio L., la Monte S.M., Squinto S., Furth M.E., Yancopoulos G.D. Submitted (JUL-1991) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 7-380 (ISOFORM 1).
[5]	Lubec G., Afjehi-Sadat L., Kang S.U. Submitted (JUL-2007) to UniProtKB Cited for: PROTEIN SEQUENCE OF 73-84 AND 183-190, MASS SPECTROMETRY. Strain: Sprague-Dawley. Tissue: Brain and Spinal cord.
[6]	"An insulin-stimulated protein kinase similar to yeast kinases involved in cell cycle control." Boulton T.G., Yancopoulos G.D., Gregory J.S., Slaughter C., Moomaw C., Hsu J., Cobb M.H. Science 249:64-67(1990) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 14-380 (ISOFORM 1), PARTIAL PROTEIN SEQUENCE.
[7]	"Molecular analysis of microtubule-associated protein-2 kinase cDNA from mouse and rat brain." de Miguel C., Kligman D., Patel J., Detera-Wadleigh S.D. DNA Cell Biol. 10:505-514(1991) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 14-380 (ISOFORM 1). Tissue: Brain cortex.
[8]	"Purification and properties of extracellular signal-regulated kinase 1, an insulin-stimulated microtubule-associated protein 2 kinase." Boulton T.G., Gregory J.S., Cobb M.H. Biochemistry 30:278-286(1991) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 43-64 AND 167-185, CHARACTERIZATION.
[9]	"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] [Europe PMC] [Abstract] Cited for: AUTOPHOSPHORYLATION.
[10]	"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] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION OF EIF4EBP1.
[11]	"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] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-203 AND TYR-205, MASS SPECTROMETRY. Tissue: Renal collecting duct.
[12]	"Regulator of G-protein signaling 14 (RGS14) is a selective H-Ras effector." Willard F.S., Willard M.D., Kimple A.J., Soundararajan M., Oestreich E.A., Li X., Sowa N.A., Kimple R.J., Doyle D.A., Der C.J., Zylka M.J., Snider W.D., Siderovski D.P. PLoS ONE 4:E4884-E4884(2009) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION IN A COMPLEX WITH BRAF; HRAS1; MAP2K1 AND RGS14.
[13]	"The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions." Yoon S., Seger R. Growth Factors 24:21-44(2006) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION.
[14]	"The ERK signaling cascade--views from different subcellular compartments." Yao Z., Seger R. BioFactors 35:407-416(2009) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION, REVIEW ON SUBCELLULAR LOCATION.
[15]	"The ERK cascade: distinct functions within various subcellular organelles." Wortzel I., Seger R. Genes Cancer 2:195-209(2011) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON ENZYME REGULATION, REVIEW ON FUNCTION.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	S46779 mRNA. Translation: AAA11604.1. X65198 mRNA. Translation: CAA46318.1. AF155236 mRNA. Translation: AAF71666.1. M61177 mRNA. Translation: AAA63486.1. M38194 mRNA. Translation: AAA41123.1. U12008 mRNA. Translation: AAA20009.1.
IPI	IPI00206172. IPI00231081.
PIR	JC1451.
RefSeq	NP_059043.1. NM_017347.2.
UniGene	Rn.2592.
3D structure databases
ProteinModelPortal	P21708.
SMR	P21708. Positions 33-375.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-487N.
IntAct	P21708. 1 interaction.
MINT	MINT-100073.
PTM databases
PhosphoSite	P21708.
Proteomic databases
PaxDb	P21708.
PRIDE	P21708.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSRNOT00000026627; ENSRNOP00000026627; ENSRNOG00000019601.
GeneID	50689.
KEGG	rno:50689.
UCSC	RGD:3046. rat.
Organism-specific databases
CTD	5595.
RGD	3046. Mapk3.
Phylogenomic databases
eggNOG	COG0515.
GeneTree	ENSGT00550000074298.
HOGENOM	HOG000233024.
HOVERGEN	HBG014652.
InParanoid	P21708.
KO	K04371.
OMA	KYQPPIM.
OrthoDB	EOG45HRXM.
Enzyme and pathway databases
BRENDA	2.7.11.24. 5301.
Gene expression databases
ArrayExpress	P21708.
Genevestigator	P21708.
GermOnline	ENSRNOG00000019601. Rattus norvegicus.
Family and domain databases
InterPro	IPR011009. Kinase-like_dom. IPR003527. MAP_kinase_CS. IPR008349. MAPK_ERK1/2. IPR000719. Prot_kinase_cat_dom. IPR017441. Protein_kinase_ATP_BS. IPR002290. Ser/Thr_dual-sp_kinase_dom. IPR008271. Ser/Thr_kinase_AS. [Graphical view]
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
ChEMBL	CHEMBL5809.
NextBio	610550.

Entry information

Entry name

MK03_RAT

Accession

Primary (citable) accession number: P21708
Secondary accession number(s): Q4PIY8, Q62686, Q9JJ13

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 1, 1991
Last sequence update:	January 23, 2007
Last modified:	May 1, 2013
This is version 151 of the entry and version 5 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program