Mitogen-Activated Protein Kinases: Specific Messages from Ubiquitous Messengers

Schaeffer, Hans J.; Weber, Michael J.

doi:10.1128/mcb.19.4.2435

Cited by 1,600Protein Kinase Regulation and GTPase SignalingMelanoma and MAPK PathwaysProtein Tyrosine Phosphatases

Mitogen-Activated Protein Kinases: Specific Messages from Ubiquitous Messengers

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Schaeffer, Hans J., Weber, Michael J.·1999·Molecular and Cellular Biology

DOI 10.1128/mcb.19.4.2435PMC PMC84036

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Abstract

Signal transduction networks allow cells to perceive changes in the extracellular environment and to mount an appropriate response. Mitogen-activated protein kinase (MAPK) cascades are among the most thoroughly studied of signal transduction systems and have been shown to participate in a diverse array of cellular programs, including cell differentiation, cell movement, cell division, and cell death. A key question in studies of this cascade is, how does a ubiquitously activated regulatory enzume generate a specific and biologically appropriate cellular response? In this review we describe recent findings that provide insight into ways that the regulation, structure, and localization of MAPKs and the participation of adapters and scaffolds can help determine biological outcomes. MAPK cascades are evolutionarily conserved in all eucaryotes and play a key role in the regulation of gene expression as well as cytoplasmic activities. They typically are organized in a three-kinase architecture consisting of a MAPK, a MAPK activator (MEK, MKK, or MAPK kinase), and a MEK activator (MEK kinase [MEKK] or MAPK kinase kinase). Transmission of signals is achieved by sequential phosphorylation and activation of the components specific to a respective cascade. In the yeast Saccharomyces cerevisiae, five MAPK modules have been described; they regulate mating, filamentation, high-osmolarity responses, cell wall remodeling, and sporulation (Fig. (Fig.1A)1A) (reviewed in references 56 and 77). In mammalian systems five distinguishable MAPK modules have been identified so far (Fig. (Fig.1B).1B). These include the extracellular signal-regulated kinase 1 and 2 (ERK1/2) cascade, which preferentially regulates cell growth and differentiation, as well as the c-Jun N-terminal kinase (JNK) and p38 MAPK cascades, which function mainly in stress responses like inflammation and apoptosis (reviewed in references 57, 74, and 103). Moreover, MAPK pathways control several developmental programs, such as morphogenesis and spatial patterning in Dictyostelium amoebae (17, 45), eye development in Drosophila melanogaster (124), vulva induction in Caenorhabditis elegans (113), and T-cell development in mammals (31). FIG. 1 Schematic overview of MAPK modules. (A) In S. cerevisiae, five MAPK modules regulate mating, filamentation, high-osmolarity responses, cell wall remodeling, and sporulation. (B) Mammalian MAPK modules regulate cell growth, differentiation, stress responses, ... Individual MAPK modules generally can signal independently from each other, and this specificity is manifested in distinct physiologic responses. This is most obvious when studying MAPK signaling in S. cerevisiae. Here a particular extracellular event characteristically activates a specific MAPK module and initiates a unique cellular program (reviewed in references 56 and 77). For example, stimulation of cells with pheromone leads to the activation of the pheromone response pathway (STE11, STE7, and FUS3) (Fig. (Fig.2),2), which ultimately results in cell cycle arrest and the induction of mating-specific genes. However, related MAPKs whose modules share some components with the pheromone response pathway are not affected by pheromone stimulation but are activated only in response to the appropriate stimulus. For example, under conditions of high osmolarity Ste11 can lead to activation of Hog1 but does not induce mating-specific genes. Conversely, conditions that activate the filamentation pathway (which utilizes STE11 and STE7) induce only genes that regulate filamentous growth without triggering pheromone responses or responses to high osmolarity. These observations suggest that yeast cells have developed efficient mechanisms to generate pathway specificity and to successfully suppress cross talk, even when individual components participate in more than one signaling pathway. FIG. 2 Scaffold and adapter molecules in MAPK pathways. MAPK scaffolds and adapters (gray shading) are thought to promote the formation of oligomeric protein complexes with components that function in a specific MAPK module. Scaffolds have been identified in ... In metazoan cells the problem is more complex because each cell is simultaneously exposed to multiple extracellular signals and must integrate these inputs to choose an appropriate response. Thus, the biological context of a signal plays a determinative role in the way that MAPK activation is interpreted. For example, although ERKs generally regulate cell growth and cell differentiation and JNKs participate in a stress response, this is not always the case and in certain cell types activation of JNKs can induce proliferation (110). This indicates that in mammalian systems physiologic responses associated with a certain MAPK module can be cell type specific. Moreover, in PC12 cells, transient stimulation of the ERK cascade leads to proliferation whereas sustained stimulation leads to differentiation,

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Four main MAPK cascades have been identified: ERK1/2, JNK, p38, and BMK1/ERK5.
“Four main MAPK cascades have been identified: ERK1/2 (extracellular signal-regulated kinases), c-Jun N-terminal kinases (JNK), p38 (p38 kinase), and the BMK1/ERK5 (big MAP kinase 1) (Schaeffer and Weber 1999).”
From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Schaeffer and Weber 1999

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Yang, S., Whitmarsh, A. J., Davis, R. J., & Sharrocks, A. D. (1998) · The EMBO Journal · doi:10.1093/emboj/17.6.1740 · Cited by 299 · see citing works
The riddle of MAP kinase signaling specificity
Madhani, H. D., & Fink, G. R. (1998) · Trends in Genetics · doi:10.1016/s0168-9525(98)01425-5 · Cited by 293 · see citing works
STE12, a protein involved in cell-type-specific transcription and signal transduction in yeast, is part of protein-DNA complexes.Preprint
Errede, B., & Ammerer, G. (1989) · Genes & Development · doi:10.1101/gad.3.9.1349 · Cited by 276 · see citing works
Leptomycin B‐sensitive nuclear export of MAPKAP kinase 2 is regulated by phosphorylation
Engel, K., Kotlyarov, A., & Gaestel, M. (1998) · The EMBO Journal · doi:10.1093/emboj/17.12.3363 · Cited by 267 · see citing works
The MAP kinase kinase kinase MLK2 co‐localizes with activated JNK along microtubules and associates with kinesin superfamily motor KIF3
Nagata, K., Puls, A., Futter, C. E., Aspenstrom, P., Schaefer, E., Nakata, T., Hirokawa, N., & Hall, A. (1998) · The EMBO Journal · doi:10.1093/emboj/17.1.149 · Cited by 263 · see citing works
Activation of the Protein Kinase p38 in the Spindle Assembly Checkpoint and Mitotic Arrest
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Inhibitory and activating functions for MAPK Kss1 in the S. cerevisiae filamentous- growth signalling pathway
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Complexes between STE5 and components of the pheromone-responsive mitogen-activated protein kinase module.
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Identification by mass spectrometry of threonine 97 in bovine myelin basic protein as a specific phosphorylation site for mitogen-activated protein kinase.
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The Ras signaling pathway in Drosophila
Wassarman, D. A., Therrien, M., & Rubin, G. M. (1995) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(95)90052-7 · Cited by 233 · see citing works
Activation of the MKK/ERK Pathway during Somatic Cell Mitosis: Direct Interactions of Active ERK with Kinetochores and Regulation of the Mitotic 3F3/2 Phosphoantigen
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Two novel targets of the MAP kinase Kss1 are negative regulators of invasive growth in the yeast Saccharomyces cerevisiae.Preprint
Cook, J. G., Bardwell, L., Kron, S. J., & Thorner, J. W. (1996) · Genes & Development · doi:10.1101/gad.10.22.2831 · Cited by 221 · see citing works
Active MAP Kinase in Mitosis: Localization at Kinetochores and Association with the Motor Protein CENP-E
Zečević, M., Catling, A. D., Eblen, S. T., Renzi, L., Hittle, J. C., Yen, T. J., Gorbsky, G. J., & Weber, M. J. (1998) · The Journal of Cell Biology · doi:10.1083/jcb.142.6.1547 · Cited by 219 · see citing works
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Extracellular signal‐regulated activation of Rap1 fails to interfere in Ras effector signalling
Zwartkruis, F. J. T., Wolthuis, R. M. F., Nabben, N. M. J. M., Franke, B., & Bos, J. L. (1998) · The EMBO Journal · doi:10.1093/emboj/17.20.5905 · Cited by 218 · see citing works
JNKK1 organizes a MAP kinase module through specific and sequential interactions with upstream and downstream components mediated by its amino-terminal extensionPreprint
Xia, Y., Wu, Z., Su, B., Murray, B. W., & Karin, M. (1998) · Genes & Development · doi:10.1101/gad.12.21.3369 · Cited by 203 · see citing works
Regulation of the MAP kinase pathway by mammalian Ksr through direct interaction with MEK and ERK
Yu, W., Fantl, W. J., Harrowe, G., & Williams, L. T. (1998) · Current Biology · doi:10.1016/s0960-9822(98)70020-x · Cited by 197 · see citing works
A Proline-Rich Sequence Unique to MEK1 and MEK2 Is Required for Raf Binding and Regulates MEK Function
Catling, A. D., Schaeffer, H. J., Reuter, C. W., Reddy, G. R., & Weber, M. J. (1995) · Molecular and Cellular Biology · doi:10.1128/mcb.15.10.5214 · Cited by 197 · see citing works
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Activation of ternary complex factor Elk-1 by stress-activated protein kinases
Gille, H., Strahl, T., & Shaw, P. E. (1995) · Current Biology · doi:10.1016/s0960-9822(95)00235-1 · Cited by 192 · see citing works
Regulation of the mating pheromone and invasive growth responses in yeast by two MAP kinase substrates
Tedford, K., Kim, S., Sa, D., Stevens, K., & Tyers, M. (1997) · Current Biology · doi:10.1016/s0960-9822(06)00118-7 · Cited by 191 · see citing works
Nuclear translocation of mitogen-activated protein kinase kinase (MEK1) in response to mitogenic stimulation
Jaaro, H., Rubinfeld, H., Hanoch, T., & Seger, R. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.8.3742 · Cited by 182 · see citing works
A Novel Regulatory Mechanism in the Mitogen-activated Protein (MAP) Kinase Cascade
Fukuda, M., Gotoh, I., Adachi, M., Gotoh, Y., & Nishida, E. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.51.32642 · Cited by 182 · see citing works
Identification of the Mitogen-Activated Protein Kinase Phosphorylation Sites on Human Sosl That Regulate Interaction with Grb2
Corbalán‐García, S., Yang, S., Degenhardt, K., & Bar‐Sagi, D. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.10.5674 · Cited by 181 · see citing works
Repression of yeast Ste12 transcription factor by direct binding of unphosphorylated Kss1 MAPK and its regulation by the Ste7 MEKPreprint
Bardwell, L., Cook, J. G., Voora, D., Baggott, D. M., Martinez, A. R., & Thorner, J. W. (1998) · Genes & Development · doi:10.1101/gad.12.18.2887 · Cited by 180 · see citing works
3pK, a Novel Mitogen-Activated Protein (MAP) Kinase-Activated Protein Kinase, Is Targeted by Three MAP Kinase Pathways
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Ran and Nuclear Transport
Moore, M. S. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.36.22857 · Cited by 175 · see citing works
Okadaic acid mimics the action of insulin in stimulating protein kinase activity in isolated adipocytes. The role of protein phosphatase 2a in attenuation of the signal.
Haystead, T., Weiel, J. E., Litchfield, D. W., Tsukitani, Y., Fischer, E. H., & Krebs, E. G. (1990) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)46261-2 · Cited by 173 · see citing works
The protein kinase KSR interacts with 14-3-3 protein and Raf
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Saccharomyces cerevisiae TEC1 is required for pseudohyphal growth
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EGF induced SOS phosphorylation in PC12 cells involves P90 RSK-2
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MEKK1 phosphorylates MEK1 and MEK2 but does not cause activation of mitogen-activated protein kinase.
Xu, S., Robbins, D. J., Frost, J. A., Dang, A., Lange, C. A., & Cobb, M. H. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.15.6808 · Cited by 157 · see citing works
Induction of Mitogen-activated Protein Kinase Phosphatase 1 by the Stress-activated Protein Kinase Signaling Pathway but Not by Extracellular Signal-regulated Kinase in Fibroblasts
Bokemeyer, D., Sorokin, A., Yan, M., Ahn, N. G., Templeton, D. J., & Dunn, M. J. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.2.639 · Cited by 157 · see citing works
Constitutive MAP kinase phosphatase (MKP-1) expression blocks G1 specific gene transcription and S-phase entry in fibroblasts.
Brondello, J., McKenzie, F. R., Sun, H., Tonks, N. K., & Pouysségur, J. (1995) · PubMed · Cited by 154 · see citing works
Jun in Drosophila development: redundant and nonredundant functions and regulation by two MAPK signal transduction pathways.Preprint
Kockel, L., Zeitlinger, J., Staszewski, L. M., Mlodzik, M., & Bohmann, D. (1997) · Genes & Development · doi:10.1101/gad.11.13.1748 · Cited by 152 · see citing works
The pool of map kinase associated with microtubules is small but constitutively active.
Morishima‐Kawashima, M., & Kosik, K. S. (1996) · Molecular Biology of the Cell · doi:10.1091/mbc.7.6.893 · Cited by 140 · see citing works
Two-way trafficking with Ran
Melchior, F., & Gerace, L. (1998) · Trends in Cell Biology · doi:10.1016/s0962-8924(98)01252-5 · Cited by 140 · see citing works
Differential Regulation of Raf-1 and B-Raf and Ras-Dependent Activation of Mitogen-Activated Protein Kinase by Cyclic AMP in PC12 Cells
Erhardt, P., Troppmair, J., Rapp, U. R., & Cooper, G. M. (1995) · Molecular and Cellular Biology · doi:10.1128/mcb.15.10.5524 · Cited by 139 · see citing works
Differential regulation of transcription: Repression by unactivated mitogen-activated protein kinase Kss1 requires the Dig1 and Dig2 proteins
Bardwell, L., Cook, J. G., Zhu-Shimoni, J. X., Voora, D., & Thorner, J. W. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.26.15400 · Cited by 138 · see citing works
Pheromone Response Elements Are Necessary and Sufficient for Basal and Pheromone-Induced Transcription of the FUS1 Gene of Saccharomyces cerevisiae
Hagen, D. C., McCaffrey, G., & Sprague, G. F. (1991) · Molecular and Cellular Biology · doi:10.1128/mcb.11.6.2952-2961.1991 · Cited by 126 · see citing works
Identification of MAP Kinase Domains by Redirecting Stress Signals into Growth Factor Responses
Brunet, A., & Pouysségur, J. (1996) · Science · doi:10.1126/science.272.5268.1652 · Cited by 125 · see citing works
Differentiation of PC12 cells in response to a cAMP analogue is accompanied by sustained activation of mitogen‐activated protein kinase
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Selective Activation of MEK1 but Not MEK2 by A-Raf from Epidermal Growth Factor-stimulated Hela Cells
Wu, X., Noh, S. J., Zhou, G., Dixon, J. E., & Guan, K. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.6.3265 · Cited by 119 · see citing works
RAS and RAF-1 Form a Signalling Complex with MEK-1 but Not MEK-2
Jelı́nek, T., Catling, A. D., Reuter, C. W., Moodie, S. A., Wolfman, A., & Weber, M. J. (1994) · Molecular and Cellular Biology · doi:10.1128/mcb.14.12.8212 · Cited by 119 · see citing works
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JUN cooperates with the ETS domain protein pointed to induce photoreceptor R7 fate in the Drosophila eye
Treier, M., Bohmann, D., & Mlodzik, M. (1995) · Cell · doi:10.1016/0092-8674(95)90188-4 · Cited by 116 · see citing works
Ste12 and Mcm1 Regulate Cell Cycle-Dependent Transcription of FAR1
Oehlen, L. J. W. M., McKinney, J. D., & Cross, F. R. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.6.2830 · Cited by 113 · see citing works
Elevation of cyclic adenosine 3',5'-monophosphate potentiates activation of mitogen-activated protein kinase by growth factors in LNCaP prostate cancer cells.
Chen, T., Cho, R. W., Stork, P. A., & Weber, M. J. (1999) · PubMed · Cited by 106 · see citing works
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A Role for Mitogen-activated Protein Kinase in the Spindle Assembly Checkpoint in XTC Cells
Wang, X. M., Zhai, Y., & Ferrell, J. E. (1997) · The Journal of Cell Biology · doi:10.1083/jcb.137.2.433 · Cited by 105 · see citing works
Modulation of Kinase Activity and Oncogenic Properties by Alternative Splicing Reveals a Novel Regulatory Mechanism for B-Raf
Papin, C., Denouel-Galy, A., Laugier, D., Calothy, G., & Eychène, A. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.38.24939 · Cited by 101 · see citing works
Mitogen-Activated Protein Kinase Kinase 1 (MKK1) Is Negatively Regulated by Threonine Phosphorylation
Rossomando, A. J., Dent, P., Sturgill, T. W., & Marshak, D. R. (1994) · Molecular and Cellular Biology · doi:10.1128/mcb.14.3.1594 · Cited by 100 · see citing works
Mitogen-Activated Protein (MAP) Kinase Phosphorylation of MAP Kinase Kinase: Determination of Phosphorylation Sites by Mass Spectrometry and Site-Directed Mutagenesis1
Mansour, S. J., Resing, K. A., Candi, J. M., Hermann, A. S., Gloor, J. W., Herskind, K. R., Wartmann, M., Davis, R. J., & Ahn, N. G. (1994) · The Journal of Biochemistry · doi:10.1093/oxfordjournals.jbchem.a124524 · Cited by 98 · see citing works
Feedback regulation of mitogen-activated protein kinase kinase kinase activity of c-Raf-1 by insulin and phorbol ester stimulation.
Ueki, K., Matsuda, S., Tobe, K., Gotoh, Y., Tamemoto, H., Yachi, M., Akanuma, Y., Yazaki, Y., Nishida, E., & Kadowaki, T. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)40745-9 · Cited by 97 · see citing works
Nucleocytoplasmic transport: Driving and directing transport
Cole, C. N., & Hammell, C. M. (1998) · Current Biology · doi:10.1016/s0960-9822(98)70239-8 · Cited by 96 · see citing works
Requirement for MAPK Activation for Normal Mitotic Progression in Xenopus Egg Extracts
Guadagno, T. M., & Ferrell, J. E. (1998) · Science · doi:10.1126/science.282.5392.1312 · Cited by 93 · see citing works
Properties of the DNA-Binding Domain of the Saccharomyces cerevisiae STE12 Protein
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Identification of signalling proteins interacting with B-Raf in the yeast two-hybrid system.
Papin, C., DENOUEL, A., Calothy, G., & Eychène, A. (1996) · PubMed · Cited by 76 · see citing works
The Dictyostelium MAP kinase ERK2 regulates multiple, independent developmental pathways.Preprint
Gaskins, C. J., Clark, A. M., Aubry, L., Segall, J. E., & Firtel, R. (1996) · Genes & Development · doi:10.1101/gad.10.1.118 · Cited by 73 · see citing works
A role for JNK/SAPK in proliferation, but not apoptosis, of IL-3-dependent cells
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Control and integration of cell signaling pathways during C. Elegans vulval development
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The MEK1 Proline-rich Insert Is Required for Efficient Activation of the Mitogen-activated Protein Kinases ERK1 and ERK2 in Mammalian Cells
Dang, A., Frost, J. A., & Cobb, M. H. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.31.19909 · Cited by 69 · see citing works
Anchoring and scaffold proteins for kinases and phosphatases.
Lester, L. B., & Scott, J. D. (1997) · PubMed · Cited by 68 · see citing works
Feedback Regulation of Raf-1 and Mitogen-activated Protein Kinase (MAP) Kinase Kinases 1 and 2 by MAP Kinase Phosphatase-1 (MKP-1)
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Yeast MEK-Dependent Signal Transduction: Response Thresholds and Parameters Affecting Fidelity
Yashar, B. M., Irie, K., Printen, J. A., Stevenson, B. J., Sprague, G. F., Matsumoto, K., & Errede, B. (1995) · Molecular and Cellular Biology · doi:10.1128/mcb.15.12.6545 · Cited by 68 · see citing works
Okadaic acid activates p42 mitogen-activated protein kinase (MAP kinase; ERK-2) in B-lymphocytes but inhibits rather than augments cellular proliferation: contrast with phorbol 12-myristate 13-acetate
Casillas, A. M., Amaral, K. C., Chegini-Farahani, S., & Nel, A. E. (1993) · Biochemical Journal · doi:10.1042/bj2900545 · Cited by 58 · see citing works
Phosphorylation of Drosophila Jun by the MAP kinase rolled regulates photoreceptor differentiation.
Peverali, F. A., Isaksson, A., Papavassiliou, A. G., Plastina, P., Staszewski, L. M., Mlodzik, M., & Bohmann, D. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb00768.x · Cited by 55 · see citing works
A novel, putative MEK kinase controls developmental timing and spatial patterning in Dictyostelium and is regulated by ubiquitin-mediated protein degradationPreprint
Chung, C. Y., Reddy, T. B. K., Zhou, K., & Firtel, R. (1998) · Genes & Development · doi:10.1101/gad.12.22.3564 · Cited by 53 · see citing works
XCL100, an inducible nuclear MAP kinase phosphatase from Xenopus laevis: Its role in MAP kinase inactivation in differentiated cells and its expression during early development
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B-Raf protein isoforms interact with and phosphorylate Mek-1 on serine residues 218 and 222.
Papin, C., Eychène, A., Brunet, A., Pagès, G., Pouysségur, J., Calothy, G., & Barnier, J. (1995) · PubMed · Cited by 41 · see citing works
Contrasting effects of two tumour promoters, phorbol myristate acetate and okadaic acid, on T-cell responses and activation of p42 MAP-kinase/ERK-2.
Amaral, M., Casillas, A. M., & Nel, A. E. (1993) · PubMed · Cited by 36 · see citing works
Feedback regulation of map kinase signal pathways
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Dissection of protein kinase and phosphatase targeting interactions.
Scott, J. D. (1997) · PubMed · Cited by 35 · see citing works

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Signal transduction by the JNK group of MAP kinases
Davis, R. J. (2000) · Cell · doi:10.1016/s0092-8674(00)00116-1 · Cited by 4,237 · see citing works
Mechanisms of type-I- and type-II-interferon-mediated signalling
Platanias, L. C. (2005) · Nature reviews. Immunology · doi:10.1038/nri1604 · Cited by 3,480 · see citing works
MAP kinase signalling pathways in cancer
Dhillon, A. S., Hagan, S., Rath, O., & Kolch, W. (2007) · Oncogene · doi:10.1038/sj.onc.1210421 · Cited by 2,995 · see citing works
“…six distinct groups of MAPKs have been characterized in mammals; extracellular signal-regulated kinase (ERK)1/2, ERK3/ 4, ERK5, ERK7/8, Jun N-terminal kinase (JNK)1/2/3 and the p38 isoforms a/b/g(ERK6)/d (Schaeffer and Weber, 1999; Chen et al., 2001b; Kyriakis and Avruch, 2001; Krens et al., 2006).”
Background
Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging
Jomova, K., Raptova, R., Alomar, S. Y., Alwasel, S. H., Nepovimova, E., Kuca, K., & Valko, M. (2023) · Archives of Toxicology · doi:10.1007/s00204-023-03562-9 · Cited by 2,638 · see citing works
Pathological roles of MAPK signaling pathways in human diseases
Kim, E. K., & Choi, E.-J. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2009.12.009 · Cited by 2,472 · see citing works
“[90] L. Resnick, M. Fennell, Targeting JNK3 for the treatment of neurodegenerative disorders, Drug Discov.”
Background
STATs in oncogenesis
Bowman, T., Garcia, R., Turkson, J., & Jove, R. (2000) · Oncogene · doi:10.1038/sj.onc.1203527 · Cited by 1,743 · see citing works
MAP Kinases in the Immune Response
Dong, C., Davis, R. J., & Flavell, R. A. (2002) · Annual Review of Immunology · doi:10.1146/annurev.immunol.20.091301.131133 · Cited by 1,660 · see citing works
ERK1/2 MAP kinases: Structure, function, and regulation
Roskoski, R. J. (2012) · Pharmacological Research · doi:10.1016/j.phrs.2012.04.005 · Cited by 1,642 · see citing works
“The following enzyme forms have been described: ERK1–ERK8, p38 / / / , and JNK1–3 [5–7].”
Background
Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions
Kölch, W. (2000) · Biochemical Journal · doi:10.1042/bj3510289 · Cited by 1,443 · see citing works
Mitogen-activated protein kinase cascades in plants: a new nomenclature
MAPK Group, Ichimura, K., Shinozaki, K., Tena, G., Sheen, J., Henry, Y., Champion, A., Kreis, M. E., Zhang, S., Heribert Hirt, A., et al. (2002) · Trends in Plant Science · doi:10.1016/s1360-1385(02)02302-6 · Cited by 1,265 · see citing works
Proteomic analysis of NMDA receptor–adhesion protein signaling complexes
Husi, H., Ward, M. A., Choudhary, J. S., Blackstock, W. P., & Grant, S. G. N. (2000) · Nature Neuroscience · doi:10.1038/76615 · Cited by 1,194 · see citing works
Unravelling cadmium toxicity and tolerance in plants: Insight into regulatory mechanisms
Gallego, S. M., Pena, L. B., Barcia, R. A., Azpilicueta, C. E., Iannone, M. F., Rosales, E. P., Zawoznik, M. S., Groppa, M. D., & Benavides, M. P. (2012) · Environmental and Experimental Botany · doi:10.1016/j.envexpbot.2012.04.006 · Cited by 1,201 · see citing works
Role of the aromatic hydrocarbon receptor and [Ah] gene battery in the oxidative stress response, cell cycle control, and apoptosis
Nebert, D. W., Roe, A. L., Dieter, M. Z., Solis, W. A., Yang, Y., & Dalton, T. P. (2000) · Biochemical Pharmacology · doi:10.1016/s0006-2952(99)00310-x · Cited by 997 · see citing works
How ERK1/2 activation controls cell proliferation and cell death: Is subcellular localization the answer?
Mebratu, Y. A., & Tesfaigzi, Y. (2009) · Cell Cycle · doi:10.4161/cc.8.8.8147 · Cited by 959 · see citing works
p38 and JNK MAPK pathways control the balance of apoptosis and autophagy in response to chemotherapeutic agents
Sui, X., Kong, N., Ye, L., Han, W., Zhou, J., Zhang, Q., He, C., & Pan, H. (2013) · Cancer Letters · doi:10.1016/j.canlet.2013.11.019 · Cited by 960 · see citing works
“So far, there are six distinct groups of MAPK have been involved in mammals—ERK1/2, ERK3/4, ERK5, ERK7/8, JNK1/2/3 and the p38 isoforms a/b/ c(ERK6)/d [3–5].”
Background
Spontaneous evolution of modularity and network motifs
Kashtan, N., & Alon, U. S. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0503610102 · Cited by 885 · see citing works
Signaling and Circuitry of Multiple MAPK Pathways Revealed by a Matrix of Global Gene Expression Profiles
Roberts, C. J., Nelson, B., Marton, M. J., Stoughton, R. B., Meyer, M. R., Bennett, H. A., He, Y. D., Dai, H. A., Walker, W. L., Hughes, T. R., et al. (2000) · Science · doi:10.1126/science.287.5454.873 · Cited by 855 · see citing works
Use of double-stranded RNA interference in <i>Drosophila</i> cell lines to dissect signal transduction pathways
Clemens, J. C., Worby, C. A., Simonson-Leff, N., Muda, M., Maehama, T., Hemmings, B. A., & Dixon, J. E. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.110149597 · Cited by 843 · see citing works
Mechanisms of action of cyclosporine.
Matsuda, S., & Koyasu, S. (2000) · Immunopharmacology · doi:10.1016/s0162-3109(00)00192-2 · Cited by 813 · see citing works
Regulation of MAP Kinase Signaling Modules by Scaffold Proteins in Mammals
Morrison, D. K., & Davis, R. J. (2003) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.19.111401.091942 · Cited by 787 · see citing works
Mechanisms in photodynamic therapy: part two—cellular signaling, cell metabolism and modes of cell death
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“MAPK subfamilies include (i) p44 and p42 MAPKs, also known as extracellular signal regulated protein kinase 1 and 2 (ERK1 and 2), (ii) p54 and p46 c-Jun N-terminal kinase 1 and 2 (JNK 1/2) and (iii) p38 MAPK (Cobb, 1999; Schaeffer and Weber, 1999; Widmann et al., 1999).”
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From receptors to stress-activated MAP kinases
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Regulatory and Signaling Properties of the Vav Family
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Mechanism of p38 MAP kinase activation in vivoPreprint
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“This phenotype of Mkk3−/− Mkk6−/− mice resembles that previously described for p38 MAPK−/− embryos (Adams et al. 2000; Allen et al. 2000; Tamura et al. 2000).”
Cellular and molecular mechanisms for immune modulation by deoxynivalenol and other trichothecenes: unraveling a paradox
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“In eukaryotes, mitogen-activated protein kinase (MAPK) pathways represent a signaling mechanism that consists of three sequentially activated protein kinases: MAPK kinase kinase (MAPKKK), MAPK kinase (MAPKK), and MAPK.(16,17) MAPKKKs are Ser/Thr protein kinases that phosphorylate MAPKKs.”
Background
Transcriptional regulation: a new dominion for inositol phosphate signaling?
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Membranes: A meeting point for lipids, proteins and therapies
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“In mammals, a number of MAPK pathways coexist, including the ERK1/2, c-Jun N-terminal kinase (JNK) and p38 MAPK cascades [237, 238].”
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Heavy Metal Stress. Activation of Distinct Mitogen-Activated Protein Kinase Pathways by Copper and Cadmium
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“MAPKs are part of a phosphorylation cascade that is composed of three sequentially activated protein kinases: MAPKKK, MAPK kinase (MAPKK), and MAPK (Schaeffer and Weber, 1999; Widmann et al., 1999).”
Background
MAP kinases and the control of nuclear events
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“Ability of different MAP kinase kinases (MAPKKs) to phosphorylate/activate Map kinases from different groups Thr-Pro-Tyr Erk ϩ ϩ Ϫ Ϫ Ϫ Ϫ Ϫ p38 Ϫ Ϫ ϩ ϩ Ϫ ϩ Ϫ JNK Ϫ Ϫ Ϫ ϩ Ϫ Ϫ ϩ Erk5 Ϫ Ϫ Ϫ Ϫ ϩ Ϫ Ϫ Mkk indicates Map kinase kinase; Erk, extracellular signal-regulated kinase; JNK, c-Jun NH2-terminal kinase; ϩ, specified Map…”
BackgroundInfluential
Mechanism of All- Trans Retinoic Acid Effect on Tumor-Associated Myeloid-Derived Suppressor Cells
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“It is likely that the events that define such specificity involve physical interactions of MAPK with other proteins (37).”
Background
Role of Nitric Oxide in Inflammation‐Mediated Neurodegeneration
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Regulation of G Protein–Initiated Signal Transduction in Yeast: Paradigms and Principles
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MAP Kinases in Fungal Pathogens
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Mechanism of Heme Oxygenase-1 Gene Activation by Cadmium in MCF-7 Mammary Epithelial Cells
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The proteasome as a target for cancer therapy.
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Inhibition of the Mitogen-Activated Protein Kinase Kinase Superfamily by a Yersinia Effector
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Cellular and molecular pharmacology of antiestrogen action and resistance.
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PI3K/Akt and CREB regulate adult neural hippocampal progenitor proliferation and differentiation
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“We also found that MEK does not strongly mediate FGF-2-induced AHNPC proliferation [Fig. 1(A)], similar to results reported in embryonic carcinoma cells (Mao and Lee, 2005), but contrasting with other findings in AHNPCs (Aberg et al., 2003) and with known roles for MEK and p38 MAP pathways in the proliferation of othe…”
Result
Inhibition of PI3K/AKT and MAPK/ERK pathways causes activation of FOXO transcription factor, leading to cell cycle arrest and apoptosis in pancreatic cancer
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“Three major groups of MAP kinases are found in mammalian cells: extracellular signal-regulated protein kinase (ERK) [92], p38 MAP kinase [93], and c-Jun N-terminal kinase (JNK) [94-96].”
Background
Localization of the MP1-MAPK Scaffold Complex to Endosomes Is Mediated by p14 and Required for Signal Transduction
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Role of Mitogen- and Stress-Activated Kinases in Ischemic Injury
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Articular cartilage functional histomorphology and mechanobiology: a research perspective
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“Activation of the 2 1 integrin collagen receptor and the 5 1 integrin fibronectin receptor in chondrocytes activates the mitogen-activated protein kinase (MAPK) pathway [105], one of the best studied, well-conserved signal transduction pathways responsible for changes in gene expression associated with proliferation,…”
Background
Activation of MAPK Cascades by G-protein-coupled Receptors: The Case of Gonadotropin-releasing Hormone Receptor
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MKK7 is an essential component of the JNK signal transduction pathway activated by proinflammatory cytokinesPreprint
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Cell adhesion molecules, signal transduction and cell growth
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Activation of Mitogen-activated Protein Kinase Pathways Induces Antioxidant Response Element-mediated Gene Expression via a Nrf2-dependent Mechanism
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Signal transduction: hanging on a scaffold
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MAPK signaling in neurodegeneration: influences of flavonoids and of nitric oxide
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Arsenic in the aetiology of cancer
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The duration, magnitude and compartmentalization of ERK MAP kinase activity: mechanisms for providing signaling specificity
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“This cannot be fully explained by cell type specificity, because ERK activation has distinct outcomes even in the same cell type (Schaeffer and Weber, 1999; Tan and Kim, 1999).”
Background
Signal transduction of ischemic preconditioning
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MAP kinase phosphatases.
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Impact of oxidative stress on lung diseases
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Molecular recognitions in the MAP kinase cascades
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Hsp72 functions as a natural inhibitory protein of c‐Jun N‐terminal kinase
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PEA-15 Mediates Cytoplasmic Sequestration of ERK MAP Kinase
Formstecher, É., Ramos, J. W., Fauquet, M., Calderwood, D., Hsieh, J.-C., Canton, B., Nguyen, X.-T., Barnier, J., Camonis, J., Ginsberg, M. H., et al. (2001) · Developmental Cell · doi:10.1016/s1534-5807(01)00035-1 · Cited by 313 · see citing works
Targeting ERK1/2 protein-serine/threonine kinases in human cancers
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“Enzymes such as MEK1/2, which catalyze the phosphorylation of tyrosine and then threonine in the activation segment of ERK1/2, make up a small group of so-called dual-specificity protein kinases [6,7].”
Background
Alternative p38 activation pathway mediated by T cell receptor-proximal tyrosine kinases
Salvador, J. M., Mittelstadt, P. R., Guszczynski, T., Copeland, T. D., Yamaguchi, H., Appella, E., Fornace, A. J., & Ashwell, J. D. (2005) · Nature Immunology · doi:10.1038/ni1177 · Cited by 306 · see citing works
“Mammalian cells have three main groups of MAPKs: extracellular signal–regulated protein kinase (Erk), c-Jun N-terminal kinase (JNK) and p38 (refs”
Background
The phosphatidylinositol 3-Kinase, p38, and extracellular signal-regulated kinase pathways are involved in osteoclast differentiation
Lee, S. E., Woo, K. M., Kim, S.-Y., Kim, H., Kwack, K., Lee, Z. H., & Kim, H.-H. (2002) · Bone · doi:10.1016/s8756-3282(01)00657-3 · Cited by 309 · see citing works
Embryonic lethality and fetal liver apoptosis in mice lacking the c‐raf‐1 gene
Mikula, M., Schreiber, M., Husak, Z., Kučerová, L., Rüth, J., Wieser, R., Zatloukal, K., Beug, H., Wagner, E. F., & Baccarini, M. (2001) · The EMBO Journal · doi:10.1093/emboj/20.8.1952 · Cited by 311 · see citing works
Activation of the ERK and AKT signalling pathway predicts poor prognosis in hepatocellular carcinoma and ERK activation in cancer tissue is associated with hepatitis C virus infection
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Mechanisms of deoxynivalenol-induced gene expression and apoptosis
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“The primary MAPK subfamilies are (1) p44 and p42 MAPKs, also known as extracellular signal regulated protein kinase 1 and 2 (ERK1 and 2); (2) p54 and p46 c-Jun N-terminal kinase 1 and 2 (JNK 1/2); and (3) p38 MAPK (Cobb 1999 ; Schaeffer and Weber 1999 ; Widmann et al.”
Background
Extracellular Signal-regulated Kinase Phosphorylates Tumor Necrosis Factor α-converting Enzyme at Threonine 735: A Potential Role in Regulated Shedding
Dı́az-Rodrı́guez, E., Montero, J. C., Esparı́s-Ogando, A., Yuste, L., & Pandiella, A. (2002) · Molecular Biology of the Cell · doi:10.1091/mbc.01-11-0561 · Cited by 308 · see citing works
Apoptotic Pathway and MAPKs Differentially Regulate Chemotropic Responses of Retinal Growth Cones
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Hyaluronan-mediated CD44 activation of RhoGTPase signaling and cytoskeleton function promotes tumor progression
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“ERKs, members of the mitogen-activated protein kinase (MAP kinase) family, are known to be activated by receptor tyrosine kinases, cytokine receptors, and G-protein-coupled receptors [100].”
Background
Targeting the Ras signaling pathway: a rational, mechanism-based treatment for hematologic malignancies?
Reuter, C. W., Morgan, M. A., & Bergmann, L. (2000) · Blood · doi:10.1182/blood.v96.5.1655 · Cited by 300 · see citing works
Microbial Elicitors Induce Activation and Dual Phosphorylation of the Arabidopsis thaliana MAPK 6
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Raf: A Strategic Target for Therapeutic Development Against Cancer
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To die or not to die for neurons in ischemia, traumatic brain injury and epilepsy: a review on the stress-activated signaling pathways and apoptotic pathways
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Intrinsic disorder in scaffold proteins: Getting more from less
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“…cascades are central cores of complex signal transduction pathways used by all eukaryotic cells to respond to a wide variety of external stimuli and regulate numerous cellular responses (Cobb, 1999; Dhanasekaran et al., 2007; Gustin et al., 1998; Schaeffer and Weber, 1999; Widmann et al., 1999).”
Background
Hydrogen sulfide‐induced apoptosis of human aorta smooth muscle cells via the activation of mitogen‐activated protein kinases and caspase‐3
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“Different MAPKs are activated by different stimuli and target at different downstream molecules and, therefore, perform different functions (21).”
Background
Identification of a docking groove on ERK and p38 MAP kinases that regulates the specificity of docking interactions
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The Stress-Induced MAP Kinase p38 Regulates Endocytic Trafficking via the GDI:Rab5 Complex
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GM1 ganglioside induces phosphorylation and activation of Trk and Erk in brain
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Role of a Mitogen-activated Protein Kinase Pathway in the Induction of Phase II Detoxifying Enzymes by Chemicals
Yu, R., Lei, W., Mandlekar, S., Weber, M. J., Der, C. J., Wu, J., & Kong, A. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.39.27545 · Cited by 281 · see citing works
Self-citation
Cellular Localization and Role of Kinase Activity of PMK1 in Magnaporthe grisea
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“In eukaryotic cells, a family of serine/threonine protein kinases known as the mitogen-activated protein (MAP) kinases is involved in transducing a variety of extracellular signals and regulating growth and differentiation processes (31, 36).”
Background
Interaction of a mitogen-activated protein kinase signaling module with the neuronal protein JIP3
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Metformin Induces Apoptosis and Cell Cycle Arrest Mediated by Oxidative Stress, AMPK and FOXO3a in MCF-7 Breast Cancer Cells
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Oxidative neuronal injury
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“the MAPKs) has been the goal of many studies in neuronal and non-neuronal cells alike [38].”
Background
Helicobacter pylori CagA Induces Ras-independent Morphogenetic Response through SHP-2 Recruitment and Activation
Higashi, H., Nakaya, A., Tsutsumi, R., Yokoyama, K., Fujii, Y., Ishikawa, S., Higuchi, M., Takahashi, A., Kurashima, Y., Teishikata, Y., et al. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m309964200 · Cited by 273 · see citing works
Kinase Suppressor of Ras (KSR) Is a Scaffold Which Facilitates Mitogen-Activated Protein Kinase Activation In Vivo
Nguyen, A., Burack, R., Stock, J. L., Kortum, R. L., Chaika, O. V., Afkarian, M., Muller, W. J., MURPHY, K. M. M., Morrison, D. K., Lewis, R. E., et al. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.9.3035-3045.2002 · Cited by 269 · see citing works
Yeast signaling pathways in the oxidative stress response
Ikner, A., & Shiozaki, K. (2004) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/j.mrfmmm.2004.09.006 · Cited by 267 · see citing works
The role of protein synthesis in memory consolidation: Progress amid decades of debate
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The Ras-Raf-MEK-ERK Pathway in the Treatment of Cancer
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Authors: Schaeffer, H. J., & Weber, M. J.
Affiliations: University of Virginia (US)
ORCID: Schaeffer, Hans J.
Weber, Michael J.
Venue: Molecular and Cellular Biology
Publisher: Informa UK Limited
Published: 1999-04
Volume: 19
Issue: 4
Pages: 2435-2444
ISSN: 0270-7306 (ISSN-L)
1098-5549
DOI: 10.1128/mcb.19.4.2435
PMC: PMC84036
OpenAlex: W1899552864
Cited by: 1,600
References: 144
Citations by year: 2026: 12 · 2025: 12 · 2024: 24 · 2023: 32 · 2022: 23 · 2021: 28 · 2020: 19 · 2019: 37 · 2018: 43 · 2017: 27 · 2016: 31 · 2015: 41 · 2014: 42 · 2013: 49 · 2012: 61
FWCI: 9.18
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Molecular and Cellular Biology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (5r01gm047332-08, 1r01ca076500-01a1)
U.S. Public Health Service
National Cancer Institute (CA-39076, CA76500)
National Institute of General Medical Sciences (GM-47332)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
Keywords: mitogen-activated protein kinase, MAPK signaling, signal transduction, ERK1/2, JNK, p38 MAPK, adaptor proteins, Saccharomyces cerevisiae, cell differentiation, stress response, apoptosis, cell growth and division
MeSH terms: Carrier Proteins, Cell Compartmentation, Fungal Proteins, Models, Biological, Morphogenesis, Protein Kinases, Saccharomyces cerevisiae, Substrate Specificity, Time Factors, Signal Transduction, Calcium-Calmodulin-Dependent Protein Kinases, Receptor Cross-Talk, Mitogen-Activated Protein Kinase Kinases, Saccharomyces cerevisiae Proteins, Adaptor Proteins, Signal Transducing

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Mitogen-Activated Protein Kinases: Specific Messages from Ubiquitous Messengers

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