P21708 (MK03_RAT) Reviewed, UniProtKB/Swiss-Prot
Last modified July 9, 2014. Version 164. History...
Names and origin
|Protein names||Recommended name:|
Mitogen-activated protein kinase 3
Short name=MAP kinase 3
Short name=MAPK 3
Extracellular signal-regulated kinase 1
Insulin-stimulated MAP2 kinase
MAP kinase isoform p44
Microtubule-associated protein 2 kinase
|Organism||Rattus norvegicus (Rat) [Reference proteome]|
|Taxonomic identifier||10116 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus|
|Sequence length||380 AA.|
|Sequence processing||The displayed sequence is further processed into a mature form.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
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.
ATP + a protein = ADP + a phosphoprotein.
Magnesium By similarity.
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.
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. Ref.12
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.
Highest levels within the nervous system, expressed in different tissues, mostly in intestine, placenta and lung.
Increased expression during development.
The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.
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
Contains 1 protein kinase domain.
|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|
|Initiator methionine||1||1||Removed Ref.3|
|Chain||2 – 380||379||Mitogen-activated protein kinase 3||PRO_0000186253|
|Domain||43 – 331||289||Protein kinase|
|Nucleotide binding||49 – 57||9||ATP By similarity|
|Motif||203 – 205||3||TXY|
|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|
|Alternative sequence||340||1||E → EVSRPPAAGRGISVPSVRPV PYCLCPQ in isoform 2.||VSP_004830|
|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|
|||"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).
|||"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).
|||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.
|||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).
|||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.
Tissue: Brain and Spinal cord.
|||"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.
|||"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.
|||"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.
|||"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.
|||"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.
|||"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].
|||"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; HRAS; MAP2K1 AND RGS14.
|||"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.
|||"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.
|||"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.|
|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.
|RefSeq||NP_059043.1. NM_017347.2. |
3D structure databases
|SMR||P21708. Positions 33-375. |
Protein-protein interaction databases
|BioGrid||248427. 3 interactions.|
|IntAct||P21708. 268 interactions.|
Protocols and materials databases
Genome annotation databases
|Ensembl||ENSRNOT00000026627; ENSRNOP00000026627; ENSRNOG00000019601. [P21708-1]|
|UCSC||RGD:3046. rat. [P21708-1]|
|RGD||3046. Mapk3. |
Enzyme and pathway databases
|BRENDA||220.127.116.11. 5301. |
Gene expression databases
Family and domain databases
|InterPro||IPR011009. Kinase-like_dom. |
|Pfam||PF00069. Pkinase. 1 hit. |
|PRINTS||PR01770. ERK1ERK2MAPK. |
|SMART||SM00220. S_TKc. 1 hit. |
|SUPFAM||SSF56112. SSF56112. 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.
|Accession||Primary (citable) accession number: P21708|
Secondary accession number(s): Q4PIY8, Q62686, Q9JJ13
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|
Index of protein domains and families