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Mitogen-Activated Protein Kinases: Specific Messages from Ubiquitous Messengers
Open accessAbstract
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 (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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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].”
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Embryonic lethality and fetal liver apoptosis in mice lacking the c‐raf‐1 gene
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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.”
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Apoptotic Pathway and MAPKs Differentially Regulate Chemotropic Responses of Retinal Growth Cones
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Alternative p38 activation pathway mediated by T cell receptor-proximal tyrosine kinases
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“Mammalian cells have three main groups of MAPKs: extracellular signal–regulated protein kinase (Erk), c-Jun N-terminal kinase (JNK) and p38 (refs”
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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].”
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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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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).”
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“Different MAPKs are activated by different stimuli and target at different downstream molecules and, therefore, perform different functions (21).”
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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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Self-citationCellular 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).”
BackgroundInteraction of a mitogen-activated protein kinase signaling module with the neuronal protein JIP3
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“the MAPKs) has been the goal of many studies in neuronal and non-neuronal cells alike [38].”
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Yeast signaling pathways in the oxidative stress response
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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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Metadata
- Authors
- Schaeffer, H. J., & Weber, M. J.
- Affiliations
- University of Virginia (US)
- 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
- PMC
- PMC84036
- OpenAlex
- W1899552864
- Semantic Scholar
- bf5b29dd374f8bafd23fa8c6a133d764aa27c83f
- 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
- 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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