| Structural highlights
Function
[MK01_RAT] 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, DCC, 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. May play a role in the spindle assembly checkpoint.[1] 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).[2] [PTN7_HUMAN] Protein phosphatase that acts preferentially on tyrosine-phosphorylated MAPK1. Plays a role in the regulation of T and B-lymphocyte development and signal transduction.[3] [4] [5] [6] [7] [8]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
MAP kinases bind activating kinases, phosphatases, and substrates through docking interactions. Here, we report a 1.9 A crystallographic analysis of inactive ERK2 bound to a "D motif" docking peptide (pepHePTP) derived from hematopoietic tyrosine phosphatase, a negative regulator of ERK2. In this complex, the complete D motif interaction defined by mutagenic analysis is observed, including extensive electrostatic interactions with the "CD" site of the kinase. Large conformational changes occur in the activation loop where the dual phosphorylation sites, which are buried in the inactive form of ERK2, become exposed to solvent in the complex. Similar conformational changes occur in a complex between ERK2 and a MEK2 (MAP/ERK kinase-2)-derived D motif peptide (pepMEK2). D motif peptides are known to bind homologous loci in the MAP kinases p38alpha and JNK1, also inducing conformational changes in these enzymes. However, the binding interactions and conformational changes are unique to each, thus contributing to specificity among MAP kinases.
Docking interactions induce exposure of activation loop in the MAP kinase ERK2.,Zhou T, Sun L, Humphreys J, Goldsmith EJ Structure. 2006 Jun;14(6):1011-9. PMID:16765894[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Ma W, Shang Y, Wei Z, Wen W, Wang W, Zhang M. Phosphorylation of DCC by ERK2 is facilitated by direct docking of the receptor P1 domain to the kinase. Structure. 2010 Nov 10;18(11):1502-11. PMID:21070949 doi:10.1016/j.str.2010.08.011
- ↑ Ma W, Shang Y, Wei Z, Wen W, Wang W, Zhang M. Phosphorylation of DCC by ERK2 is facilitated by direct docking of the receptor P1 domain to the kinase. Structure. 2010 Nov 10;18(11):1502-11. PMID:21070949 doi:10.1016/j.str.2010.08.011
- ↑ Adachi M, Sekiya M, Isobe M, Kumura Y, Ogita Z, Hinoda Y, Imai K, Yachi A. Molecular cloning and chromosomal mapping of a human protein-tyrosine phosphatase LC-PTP. Biochem Biophys Res Commun. 1992 Aug 14;186(3):1607-15. PMID:1510684
- ↑ Zanke B, Suzuki H, Kishihara K, Mizzen L, Minden M, Pawson A, Mak TW. Cloning and expression of an inducible lymphoid-specific, protein tyrosine phosphatase (HePTPase). Eur J Immunol. 1992 Jan;22(1):235-9. PMID:1530918 doi:http://dx.doi.org/10.1002/eji.1830220134
- ↑ Saxena M, Williams S, Gilman J, Mustelin T. Negative regulation of T cell antigen receptor signal transduction by hematopoietic tyrosine phosphatase (HePTP). J Biol Chem. 1998 Jun 19;273(25):15340-4. PMID:9624114
- ↑ Saxena M, Williams S, Brockdorff J, Gilman J, Mustelin T. Inhibition of T cell signaling by mitogen-activated protein kinase-targeted hematopoietic tyrosine phosphatase (HePTP). J Biol Chem. 1999 Apr 23;274(17):11693-700. PMID:10206983
- ↑ Saxena M, Williams S, Tasken K, Mustelin T. Crosstalk between cAMP-dependent kinase and MAP kinase through a protein tyrosine phosphatase. Nat Cell Biol. 1999 Sep;1(5):305-11. PMID:10559944 doi:http://dx.doi.org/10.1038/13024
- ↑ Pettiford SM, Herbst R. The MAP-kinase ERK2 is a specific substrate of the protein tyrosine phosphatase HePTP. Oncogene. 2000 Feb 17;19(7):858-69. PMID:10702794 doi:http://dx.doi.org/10.1038/sj.onc.1203408
- ↑ Zhou T, Sun L, Humphreys J, Goldsmith EJ. Docking interactions induce exposure of activation loop in the MAP kinase ERK2. Structure. 2006 Jun;14(6):1011-9. PMID:16765894 doi:10.1016/j.str.2006.04.006
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