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P21708

- MK03_RAT

UniProt

P21708 - MK03_RAT

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Protein

Mitogen-activated protein kinase 3

Gene

Mapk3

Organism
Rattus norvegicus (Rat)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli

Functioni

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 activityi

ATP + a protein = ADP + a phosphoprotein.

Cofactori

Magnesium.By similarity

Enzyme regulationi

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.

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei72 – 721ATPPROSITE-ProRule annotation
Active sitei167 – 1671Proton acceptorPROSITE-ProRule annotation

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi49 – 579ATPPROSITE-ProRule annotation

GO - Molecular functioni

  1. ATP binding Source: RGD
  2. MAP kinase activity Source: UniProtKB
  3. protein serine/threonine kinase activity Source: RGD

GO - Biological processi

  1. apoptotic process Source: UniProtKB-KW
  2. arachidonic acid metabolic process Source: RGD
  3. caveolin-mediated endocytosis Source: UniProtKB
  4. cell cycle Source: UniProtKB-KW
  5. intracellular signal transduction Source: RGD
  6. MAPK cascade Source: RGD
  7. MAPK import into nucleus Source: RGD
  8. peptidyl-serine phosphorylation Source: RGD
  9. positive regulation of transcription, DNA-templated Source: RGD
  10. positive regulation of translation Source: RGD
  11. protein complex assembly Source: UniProtKB
  12. protein phosphorylation Source: RGD
  13. regulation of cytoskeleton organization Source: UniProtKB
  14. regulation of early endosome to late endosome transport Source: UniProtKB
  15. regulation of Golgi inheritance Source: UniProtKB
  16. regulation of stress-activated MAPK cascade Source: UniProtKB
  17. response to epidermal growth factor Source: UniProtKB
  18. response to toxic substance Source: RGD
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Biological processi

Apoptosis, Cell cycle

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.11.24. 5301.

Names & Taxonomyi

Protein namesi
Recommended name:
Mitogen-activated protein kinase 3 (EC:2.7.11.24)
Short name:
MAP kinase 3
Short name:
MAPK 3
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 namesi
Name:Mapk3
Synonyms:Erk1, Prkm3
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
ProteomesiUP000002494: Chromosome 1

Organism-specific databases

RGDi3046. Mapk3.

Subcellular locationi

Cytoplasm By similarity. Nucleus
Note: Autophosphorylation at Thr-207 promotes nuclear localization. PEA15-binding redirects the biological outcome of MAPK3 kinase-signaling by sequestering MAPK3 into the cytoplasm.By similarity

GO - Cellular componenti

  1. caveola Source: UniProtKB
  2. cytoskeleton Source: UniProtKB
  3. cytosol Source: UniProtKB
  4. early endosome Source: UniProtKB
  5. focal adhesion Source: UniProtKB
  6. Golgi apparatus Source: UniProtKB
  7. late endosome Source: UniProtKB
  8. mitochondrion Source: UniProtKB
  9. nucleoplasm Source: UniProtKB
  10. nucleus Source: UniProtKB
  11. protein complex Source: RGD
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Initiator methioninei1 – 11Removed1 Publication
Chaini2 – 380379Mitogen-activated protein kinase 3PRO_0000186253Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei2 – 21N-acetylalanine1 Publication
Modified residuei171 – 1711PhosphoserineBy similarity
Modified residuei199 – 1991PhosphothreonineBy similarity
Modified residuei203 – 2031Phosphothreonine; by MAP2K1 and MAP2K22 Publications
Modified residuei205 – 2051Phosphotyrosine; by MAP2K1 and MAP2K22 Publications
Modified residuei208 – 2081Phosphothreonine; by autocatalysisBy similarity

Post-translational modificationi

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.By similarity3 Publications

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

PaxDbiP21708.
PRIDEiP21708.

PTM databases

PhosphoSiteiP21708.

Expressioni

Tissue specificityi

Highest levels within the nervous system, expressed in different tissues, mostly in intestine, placenta and lung.

Developmental stagei

Increased expression during development.

Gene expression databases

GenevestigatoriP21708.

Interactioni

Subunit structurei

Binds both upstream activators and downstream substrates in multimolecular complexes. Found in a complex with at least BRAF, HRAS, 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).By similarity

Protein-protein interaction databases

BioGridi248427. 3 interactions.
DIPiDIP-487N.
IntActiP21708. 268 interactions.
MINTiMINT-100073.

Structurei

3D structure databases

ProteinModelPortaliP21708.
SMRiP21708. Positions 33-375.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini43 – 331289Protein kinasePROSITE-ProRule annotationAdd
BLAST

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi203 – 2053TXY

Domaini

The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.

Sequence similaritiesi

Contains 1 protein kinase domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiCOG0515.
GeneTreeiENSGT00550000074298.
HOGENOMiHOG000233024.
HOVERGENiHBG014652.
InParanoidiP21708.
KOiK04371.
OMAiGPRYTDL.
OrthoDBiEOG7M3J0K.
PhylomeDBiP21708.
TreeFamiTF105097.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR003527. MAP_kinase_CS.
IPR008349. MAPK_ERK1/2.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
PRINTSiPR01770. ERK1ERK2MAPK.
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS01351. MAPK. 1 hit.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. Align

Isoform 1 (identifier: P21708-1) [UniParc]FASTAAdd to Basket

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.

« Hide

        10         20         30         40         50
MAAAAAAPGG GGGEPRGTAG VVPVVPGEVE VVKGQPFDVG PRYTQLQYIG
60 70 80 90 100
EGAYGMVSSA YDHVRKTRVA IKKISPFEHQ TYCQRTLREI QILLRFRHEN
110 120 130 140 150
VIGIRDILRA PTLEAMRDVY IVQDLMETDL YKLLKSQQLS NDHICYFLYQ
160 170 180 190 200
ILRGLKYIHS ANVLHRDLKP SNLLINTTCD LKICDFGLAR IADPEHDHTG
210 220 230 240 250
FLTEYVATRW YRAPEIMLNS KGYTKSIDIW SVGCILAEML SNRPIFPGKH
260 270 280 290 300
YLDQLNHILG ILGSPSQEDL NCIINMKARN YLQSLPSKTK VAWAKLFPKS
310 320 330 340 350
DSKALDLLDR MLTFNPNKRI TVEEALAHPY LEQYYDPTDE PVAEEPFTFD
360 370 380
MELDDLPKER LKELIFQETA RFQPGAPEAP
Length:380
Mass (Da):43,081
Last modified:January 23, 2007 - v5
Checksum:i49C4EA95B627237F
GO
Isoform 2 (identifier: P21708-2) [UniParc]FASTAAdd to Basket

Also known as: B

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

Show »
Length:406
Mass (Da):45,770
Checksum:i2F40B2DFA5A116B0
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti95 – 951R → G in AAA11604. (PubMed:1327976)Curated
Sequence conflicti95 – 951R → G in CAA46318. (PubMed:1327976)Curated
Sequence conflicti95 – 951R → G in AAA63486. 1 PublicationCurated
Sequence conflicti95 – 951R → G in AAA20009. (PubMed:1716439)Curated

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei340 – 3401E → EVSRPPAAGRGISVPSVRPV PYCLCPQ in isoform 2. 1 PublicationVSP_004830

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
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.
PIRiJC1451.
RefSeqiNP_059043.1. NM_017347.2.
UniGeneiRn.2592.

Genome annotation databases

EnsembliENSRNOT00000026627; ENSRNOP00000026627; ENSRNOG00000019601. [P21708-1]
GeneIDi50689.
KEGGirno:50689.
UCSCiRGD:3046. rat. [P21708-1]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
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 .
PIRi JC1451.
RefSeqi NP_059043.1. NM_017347.2.
UniGenei Rn.2592.

3D structure databases

ProteinModelPortali P21708.
SMRi P21708. Positions 33-375.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 248427. 3 interactions.
DIPi DIP-487N.
IntActi P21708. 268 interactions.
MINTi MINT-100073.

Chemistry

ChEMBLi CHEMBL5809.

PTM databases

PhosphoSitei P21708.

Proteomic databases

PaxDbi P21708.
PRIDEi P21708.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENSRNOT00000026627 ; ENSRNOP00000026627 ; ENSRNOG00000019601 . [P21708-1 ]
GeneIDi 50689.
KEGGi rno:50689.
UCSCi RGD:3046. rat. [P21708-1 ]

Organism-specific databases

CTDi 5595.
RGDi 3046. Mapk3.

Phylogenomic databases

eggNOGi COG0515.
GeneTreei ENSGT00550000074298.
HOGENOMi HOG000233024.
HOVERGENi HBG014652.
InParanoidi P21708.
KOi K04371.
OMAi GPRYTDL.
OrthoDBi EOG7M3J0K.
PhylomeDBi P21708.
TreeFami TF105097.

Enzyme and pathway databases

BRENDAi 2.7.11.24. 5301.

Miscellaneous databases

NextBioi 610550.
PROi P21708.

Gene expression databases

Genevestigatori P21708.

Family and domain databases

InterProi IPR011009. Kinase-like_dom.
IPR003527. MAP_kinase_CS.
IPR008349. MAPK_ERK1/2.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view ]
Pfami PF00069. Pkinase. 1 hit.
[Graphical view ]
PRINTSi PR01770. ERK1ERK2MAPK.
SMARTi SM00220. S_TKc. 1 hit.
[Graphical view ]
SUPFAMi SSF56112. SSF56112. 1 hit.
PROSITEi PS01351. MAPK. 1 hit.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  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, IDENTIFICATION BY MASS SPECTROMETRY.
    Tissue: Pheochromocytoma.
  4. 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, IDENTIFICATION BY 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, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
  12. Cited for: IDENTIFICATION IN A COMPLEX WITH BRAF; HRAS; 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.

Entry informationi

Entry nameiMK03_RAT
AccessioniPrimary (citable) accession number: P21708
Secondary accession number(s): Q4PIY8, Q62686, Q9JJ13
Entry historyi
Integrated into UniProtKB/Swiss-Prot: May 1, 1991
Last sequence update: January 23, 2007
Last modified: October 29, 2014
This is version 166 of the entry and version 5 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3