| Structural highlights
Function
MK01_HUMAN 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] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] 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.[24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46]
Publication Abstract from PubMed
Mitogen-activated protein kinases (MAPKs) have a docking groove that interacts with linear "docking" motifs in binding partners. To determine the structural basis of binding specificity between MAPKs and docking motifs, we quantitatively analyzed the ability of 15 docking motifs from diverse MAPK partners to bind to c-Jun amino-terminal kinase 1 (JNK1), p38alpha, and extracellular signal-regulated kinase 2 (ERK2). Classical docking motifs mediated highly specific binding only to JNK1, and only those motifs with a sequence pattern distinct from the classical MAPK binding docking motif consensus differentiated between the topographically similar docking grooves of ERK and p38alpha. Crystal structures of four complexes of MAPKs with docking peptides, representing JNK-specific, ERK-specific, or ERK- and p38-selective binding modes, revealed that the regions located between consensus positions in the docking motifs showed conformational diversity. Although the consensus positions in the docking motifs served as anchor points that bound to common MAPK surface features and mostly contributed to docking in a nondiscriminatory fashion, the conformation of the intervening region between the anchor points mostly determined specificity. We designed peptides with tailored MAPK binding profiles by rationally changing the length and amino acid composition of intervening regions located between anchor points. These results suggest a coherent structural model for MAPK docking specificity that reveals how short linear motifs binding to a common kinase docking groove can mediate diverse interaction patterns and contribute to correct MAPK partner selection in signaling networks.
Specificity of linear motifs that bind to a common mitogen-activated protein kinase docking groove.,Garai A, Zeke A, Gogl G, Toro I, Fordos F, Blankenburg H, Barkai T, Varga J, Alexa A, Emig D, Albrecht M, Remenyi A Sci Signal. 2012 Oct 9;5(245):ra74. doi: 10.1126/scisignal.2003004. PMID:23047924[47]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Sgouras DN, Athanasiou MA, Beal GJ Jr, Fisher RJ, Blair DG, Mavrothalassitis GJ. ERF: an ETS domain protein with strong transcriptional repressor activity, can suppress ets-associated tumorigenesis and is regulated by phosphorylation during cell cycle and mitogenic stimulation. EMBO J. 1995 Oct 2;14(19):4781-93. PMID:7588608
- ↑ Sithanandam G, Latif F, Duh FM, Bernal R, Smola U, Li H, Kuzmin I, Wixler V, Geil L, Shrestha S. 3pK, a new mitogen-activated protein kinase-activated protein kinase located in the small cell lung cancer tumor suppressor gene region. Mol Cell Biol. 1996 Mar;16(3):868-76. PMID:8622688
- ↑ Ni H, Wang XS, Diener K, Yao Z. MAPKAPK5, a novel mitogen-activated protein kinase (MAPK)-activated protein kinase, is a substrate of the extracellular-regulated kinase (ERK) and p38 kinase. Biochem Biophys Res Commun. 1998 Feb 13;243(2):492-6. PMID:9480836 doi:S0006-291X(98)98135-9
- ↑ Deak M, Clifton AD, Lucocq LM, Alessi DR. Mitogen- and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB. EMBO J. 1998 Aug 3;17(15):4426-41. PMID:9687510 doi:10.1093/emboj/17.15.4426
- ↑ Niu H, Ye BH, Dalla-Favera R. Antigen receptor signaling induces MAP kinase-mediated phosphorylation and degradation of the BCL-6 transcription factor. Genes Dev. 1998 Jul 1;12(13):1953-61. PMID:9649500
- ↑ Camps M, Nichols A, Gillieron C, Antonsson B, Muda M, Chabert C, Boschert U, Arkinstall S. Catalytic activation of the phosphatase MKP-3 by ERK2 mitogen-activated protein kinase. Science. 1998 May 22;280(5367):1262-5. PMID:9596579
- ↑ Cruzalegui FH, Cano E, Treisman R. ERK activation induces phosphorylation of Elk-1 at multiple S/T-P motifs to high stoichiometry. Oncogene. 1999 Dec 23;18(56):7948-57. PMID:10637505 doi:10.1038/sj.onc.1203362
- ↑ Brondello JM, Pouyssegur J, McKenzie FR. Reduced MAP kinase phosphatase-1 degradation after p42/p44MAPK-dependent phosphorylation. Science. 1999 Dec 24;286(5449):2514-7. PMID:10617468
- ↑ Scheper GC, Morrice NA, Kleijn M, Proud CG. The mitogen-activated protein kinase signal-integrating kinase Mnk2 is a eukaryotic initiation factor 4E kinase with high levels of basal activity in mammalian cells. Mol Cell Biol. 2001 Feb;21(3):743-54. PMID:11154262 doi:10.1128/MCB.21.3.743-754.2001
- ↑ Ouwens DM, de Ruiter ND, van der Zon GC, Carter AP, Schouten J, van der Burgt C, Kooistra K, Bos JL, Maassen JA, van Dam H. Growth factors can activate ATF2 via a two-step mechanism: phosphorylation of Thr71 through the Ras-MEK-ERK pathway and of Thr69 through RalGDS-Src-p38. EMBO J. 2002 Jul 15;21(14):3782-93. PMID:12110590 doi:10.1093/emboj/cdf361
- ↑ Garcia J, Ye Y, Arranz V, Letourneux C, Pezeron G, Porteu F. IEX-1: a new ERK substrate involved in both ERK survival activity and ERK activation. EMBO J. 2002 Oct 1;21(19):5151-63. PMID:12356731
- ↑ Wu Y, Chen Z, Ullrich A. EGFR and FGFR signaling through FRS2 is subject to negative feedback control by ERK1/2. Biol Chem. 2003 Aug;384(8):1215-26. PMID:12974390 doi:https://dx.doi.org/10.1515/BC.2003.134
- ↑ Masuda K, Shima H, Katagiri C, Kikuchi K. Activation of ERK induces phosphorylation of MAPK phosphatase-7, a JNK specific phosphatase, at Ser-446. J Biol Chem. 2003 Aug 22;278(34):32448-56. Epub 2003 Jun 6. PMID:12794087 doi:10.1074/jbc.M213254200
- ↑ Allan LA, Morrice N, Brady S, Magee G, Pathak S, Clarke PR. Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK. Nat Cell Biol. 2003 Jul;5(7):647-54. PMID:12792650 doi:10.1038/ncb1005
- ↑ Mitsushima M, Suwa A, Amachi T, Ueda K, Kioka N. Extracellular signal-regulated kinase activated by epidermal growth factor and cell adhesion interacts with and phosphorylates vinexin. J Biol Chem. 2004 Aug 13;279(33):34570-7. Epub 2004 Jun 7. PMID:15184391 doi:10.1074/jbc.M402304200
- ↑ Domina AM, Vrana JA, Gregory MA, Hann SR, Craig RW. MCL1 is phosphorylated in the PEST region and stabilized upon ERK activation in viable cells, and at additional sites with cytotoxic okadaic acid or taxol. Oncogene. 2004 Jul 8;23(31):5301-15. PMID:15241487 doi:10.1038/sj.onc.1207692
- ↑ Langlais P, Wang C, Dong LQ, Carroll CA, Weintraub ST, Liu F. Phosphorylation of Grb10 by mitogen-activated protein kinase: identification of Ser150 and Ser476 of human Grb10zeta as major phosphorylation sites. Biochemistry. 2005 Jun 21;44(24):8890-7. PMID:15952796 doi:10.1021/bi050413i
- ↑ Chen CH, Wang WJ, Kuo JC, Tsai HC, Lin JR, Chang ZF, Chen RH. Bidirectional signals transduced by DAPK-ERK interaction promote the apoptotic effect of DAPK. EMBO J. 2005 Jan 26;24(2):294-304. Epub 2004 Dec 16. PMID:15616583 doi:10.1038/sj.emboj.7600510
- ↑ Hong JW, Ryu MS, Lim IK. Phosphorylation of serine 147 of tis21/BTG2/pc3 by p-Erk1/2 induces Pin-1 binding in cytoplasm and cell death. J Biol Chem. 2005 Jun 3;280(22):21256-63. Epub 2005 Mar 23. PMID:15788397 doi:10.1074/jbc.M500318200
- ↑ Dougherty MK, Muller J, Ritt DA, Zhou M, Zhou XZ, Copeland TD, Conrads TP, Veenstra TD, Lu KP, Morrison DK. Regulation of Raf-1 by direct feedback phosphorylation. Mol Cell. 2005 Jan 21;17(2):215-24. PMID:15664191 doi:10.1016/j.molcel.2004.11.055
- ↑ Hu Y, Mivechi NF. Association and regulation of heat shock transcription factor 4b with both extracellular signal-regulated kinase mitogen-activated protein kinase and dual-specificity tyrosine phosphatase DUSP26. Mol Cell Biol. 2006 Apr;26(8):3282-94. PMID:16581800 doi:26/8/3282
- ↑ Hu S, Xie Z, Onishi A, Yu X, Jiang L, Lin J, Rho HS, Woodard C, Wang H, Jeong JS, Long S, He X, Wade H, Blackshaw S, Qian J, Zhu H. Profiling the human protein-DNA interactome reveals ERK2 as a transcriptional repressor of interferon signaling. Cell. 2009 Oct 30;139(3):610-22. doi: 10.1016/j.cell.2009.08.037. PMID:19879846 doi:10.1016/j.cell.2009.08.037
- ↑ Sun J, Pedersen M, Ronnstrand L. The D816V mutation of c-Kit circumvents a requirement for Src family kinases in c-Kit signal transduction. J Biol Chem. 2009 Apr 24;284(17):11039-47. doi: 10.1074/jbc.M808058200. Epub 2009, Mar 5. PMID:19265199 doi:10.1074/jbc.M808058200
- ↑ Sgouras DN, Athanasiou MA, Beal GJ Jr, Fisher RJ, Blair DG, Mavrothalassitis GJ. ERF: an ETS domain protein with strong transcriptional repressor activity, can suppress ets-associated tumorigenesis and is regulated by phosphorylation during cell cycle and mitogenic stimulation. EMBO J. 1995 Oct 2;14(19):4781-93. PMID:7588608
- ↑ Sithanandam G, Latif F, Duh FM, Bernal R, Smola U, Li H, Kuzmin I, Wixler V, Geil L, Shrestha S. 3pK, a new mitogen-activated protein kinase-activated protein kinase located in the small cell lung cancer tumor suppressor gene region. Mol Cell Biol. 1996 Mar;16(3):868-76. PMID:8622688
- ↑ Ni H, Wang XS, Diener K, Yao Z. MAPKAPK5, a novel mitogen-activated protein kinase (MAPK)-activated protein kinase, is a substrate of the extracellular-regulated kinase (ERK) and p38 kinase. Biochem Biophys Res Commun. 1998 Feb 13;243(2):492-6. PMID:9480836 doi:S0006-291X(98)98135-9
- ↑ Deak M, Clifton AD, Lucocq LM, Alessi DR. Mitogen- and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB. EMBO J. 1998 Aug 3;17(15):4426-41. PMID:9687510 doi:10.1093/emboj/17.15.4426
- ↑ Niu H, Ye BH, Dalla-Favera R. Antigen receptor signaling induces MAP kinase-mediated phosphorylation and degradation of the BCL-6 transcription factor. Genes Dev. 1998 Jul 1;12(13):1953-61. PMID:9649500
- ↑ Camps M, Nichols A, Gillieron C, Antonsson B, Muda M, Chabert C, Boschert U, Arkinstall S. Catalytic activation of the phosphatase MKP-3 by ERK2 mitogen-activated protein kinase. Science. 1998 May 22;280(5367):1262-5. PMID:9596579
- ↑ Cruzalegui FH, Cano E, Treisman R. ERK activation induces phosphorylation of Elk-1 at multiple S/T-P motifs to high stoichiometry. Oncogene. 1999 Dec 23;18(56):7948-57. PMID:10637505 doi:10.1038/sj.onc.1203362
- ↑ Brondello JM, Pouyssegur J, McKenzie FR. Reduced MAP kinase phosphatase-1 degradation after p42/p44MAPK-dependent phosphorylation. Science. 1999 Dec 24;286(5449):2514-7. PMID:10617468
- ↑ Scheper GC, Morrice NA, Kleijn M, Proud CG. The mitogen-activated protein kinase signal-integrating kinase Mnk2 is a eukaryotic initiation factor 4E kinase with high levels of basal activity in mammalian cells. Mol Cell Biol. 2001 Feb;21(3):743-54. PMID:11154262 doi:10.1128/MCB.21.3.743-754.2001
- ↑ Ouwens DM, de Ruiter ND, van der Zon GC, Carter AP, Schouten J, van der Burgt C, Kooistra K, Bos JL, Maassen JA, van Dam H. Growth factors can activate ATF2 via a two-step mechanism: phosphorylation of Thr71 through the Ras-MEK-ERK pathway and of Thr69 through RalGDS-Src-p38. EMBO J. 2002 Jul 15;21(14):3782-93. PMID:12110590 doi:10.1093/emboj/cdf361
- ↑ Garcia J, Ye Y, Arranz V, Letourneux C, Pezeron G, Porteu F. IEX-1: a new ERK substrate involved in both ERK survival activity and ERK activation. EMBO J. 2002 Oct 1;21(19):5151-63. PMID:12356731
- ↑ Wu Y, Chen Z, Ullrich A. EGFR and FGFR signaling through FRS2 is subject to negative feedback control by ERK1/2. Biol Chem. 2003 Aug;384(8):1215-26. PMID:12974390 doi:https://dx.doi.org/10.1515/BC.2003.134
- ↑ Masuda K, Shima H, Katagiri C, Kikuchi K. Activation of ERK induces phosphorylation of MAPK phosphatase-7, a JNK specific phosphatase, at Ser-446. J Biol Chem. 2003 Aug 22;278(34):32448-56. Epub 2003 Jun 6. PMID:12794087 doi:10.1074/jbc.M213254200
- ↑ Allan LA, Morrice N, Brady S, Magee G, Pathak S, Clarke PR. Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK. Nat Cell Biol. 2003 Jul;5(7):647-54. PMID:12792650 doi:10.1038/ncb1005
- ↑ Mitsushima M, Suwa A, Amachi T, Ueda K, Kioka N. Extracellular signal-regulated kinase activated by epidermal growth factor and cell adhesion interacts with and phosphorylates vinexin. J Biol Chem. 2004 Aug 13;279(33):34570-7. Epub 2004 Jun 7. PMID:15184391 doi:10.1074/jbc.M402304200
- ↑ Domina AM, Vrana JA, Gregory MA, Hann SR, Craig RW. MCL1 is phosphorylated in the PEST region and stabilized upon ERK activation in viable cells, and at additional sites with cytotoxic okadaic acid or taxol. Oncogene. 2004 Jul 8;23(31):5301-15. PMID:15241487 doi:10.1038/sj.onc.1207692
- ↑ Langlais P, Wang C, Dong LQ, Carroll CA, Weintraub ST, Liu F. Phosphorylation of Grb10 by mitogen-activated protein kinase: identification of Ser150 and Ser476 of human Grb10zeta as major phosphorylation sites. Biochemistry. 2005 Jun 21;44(24):8890-7. PMID:15952796 doi:10.1021/bi050413i
- ↑ Chen CH, Wang WJ, Kuo JC, Tsai HC, Lin JR, Chang ZF, Chen RH. Bidirectional signals transduced by DAPK-ERK interaction promote the apoptotic effect of DAPK. EMBO J. 2005 Jan 26;24(2):294-304. Epub 2004 Dec 16. PMID:15616583 doi:10.1038/sj.emboj.7600510
- ↑ Hong JW, Ryu MS, Lim IK. Phosphorylation of serine 147 of tis21/BTG2/pc3 by p-Erk1/2 induces Pin-1 binding in cytoplasm and cell death. J Biol Chem. 2005 Jun 3;280(22):21256-63. Epub 2005 Mar 23. PMID:15788397 doi:10.1074/jbc.M500318200
- ↑ Dougherty MK, Muller J, Ritt DA, Zhou M, Zhou XZ, Copeland TD, Conrads TP, Veenstra TD, Lu KP, Morrison DK. Regulation of Raf-1 by direct feedback phosphorylation. Mol Cell. 2005 Jan 21;17(2):215-24. PMID:15664191 doi:10.1016/j.molcel.2004.11.055
- ↑ Hu Y, Mivechi NF. Association and regulation of heat shock transcription factor 4b with both extracellular signal-regulated kinase mitogen-activated protein kinase and dual-specificity tyrosine phosphatase DUSP26. Mol Cell Biol. 2006 Apr;26(8):3282-94. PMID:16581800 doi:26/8/3282
- ↑ Hu S, Xie Z, Onishi A, Yu X, Jiang L, Lin J, Rho HS, Woodard C, Wang H, Jeong JS, Long S, He X, Wade H, Blackshaw S, Qian J, Zhu H. Profiling the human protein-DNA interactome reveals ERK2 as a transcriptional repressor of interferon signaling. Cell. 2009 Oct 30;139(3):610-22. doi: 10.1016/j.cell.2009.08.037. PMID:19879846 doi:10.1016/j.cell.2009.08.037
- ↑ Sun J, Pedersen M, Ronnstrand L. The D816V mutation of c-Kit circumvents a requirement for Src family kinases in c-Kit signal transduction. J Biol Chem. 2009 Apr 24;284(17):11039-47. doi: 10.1074/jbc.M808058200. Epub 2009, Mar 5. PMID:19265199 doi:10.1074/jbc.M808058200
- ↑ Garai A, Zeke A, Gogl G, Toro I, Fordos F, Blankenburg H, Barkai T, Varga J, Alexa A, Emig D, Albrecht M, Remenyi A. Specificity of linear motifs that bind to a common mitogen-activated protein kinase docking groove. Sci Signal. 2012 Oct 9;5(245):ra74. doi: 10.1126/scisignal.2003004. PMID:23047924 doi:https://dx.doi.org/10.1126/scisignal.2003004
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