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

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Mitogen-Activated Protein Kinases: Specific Messages from Ubiquitous Messengers

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

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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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Background
Development of T-cell lymphomas in Eμ-IEX-1 mice
Zhang, Y., Finegold, M. J., Porteu, F., Kanteti, P. V. S., & Wu, M. X. (2003) · Oncogene · doi:10.1038/sj.onc.1206707 · Cited by 29
Role of Regulatory Elements and the MAPK/ERK or p38 MAPK Pathways for Activation of Human Cytomegalovirus Gene Expression
Chen, J., & Stinski, M. F. (2002) · Journal of Virology · doi:10.1128/jvi.76.10.4873-4885.2002 · Cited by 29
A Potential Role for Mini-chromosome Maintenance (MCM) Proteins in Initiation at the Dihydrofolate Reductase Replication Origin
Alexandrow, M. G., Ritzi, M., Pemov, A., & Hamlin, J. L. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m108118200 · Cited by 29
MEK partner 1 (MP1): Regulation of oligomerization in MAP kinase signaling
Sharma, C., Vomastek, T., Tarcsafalvi, A., Catling, A. D., Schaeffer, H. J., Eblen, S. T., & Weber, M. J. (2004) · Journal of Cellular Biochemistry · doi:10.1002/jcb.20344 · Cited by 29
Self-citation
The scaffold protein IB1/JIP-1 controls the activation of JNK in rat stressed urothelium
Tawadros, T., Formenton, A., Dudler, J., Thompson, N. A., NICOD, P. H., Leisinger, H., Waeber, G., & Haefliger, J. (2002) · Journal of Cell Science · doi:10.1242/jcs.115.2.385 · Cited by 29
Negative Regulation of the Sapk/Jnk Signaling Pathway by Presenilin 1
Kim, J. W., Chang, T.-S., Lee, J. E., Huh, S., Yeon, S. W., Yang, W. S., Joe, C. O., Mook‐Jung, I., Tanzi, R. E., Kim, T., et al. (2001) · The Journal of Cell Biology · doi:10.1083/jcb.153.3.457 · Cited by 29
Honokiol inhibits H2O2-induced apoptosis in human lens epithelial cells via inhibition of the mitogen-activated protein kinase and Akt pathways
Tang, X., Yao, K., Zhang, L., Yang, Y., & Yao, H. (2011) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2010.09.076 · Cited by 28
Activation of extracellular regulated kinases (ERK1/2) predicts poor prognosis in urothelial bladder carcinoma and is not associated with B-Raf gene mutations
Κάρλου, Μ., Saetta, A. A., Korkolopoulou, P. A., Levidou, G., Papanastasiou, P., Boltetsou, E., Isaiadis, D., Pavlopoulos, P. M., Thymara, I., Thomas-Tsagli, E., et al. (2009) · Pathology · doi:10.1080/00313020902885011 · Cited by 28
Hyperactivation of MEK/ERK pathway by Ca 2+ /calmodulin‐dependent protein kinase kinase 2 promotes cellular proliferation by activating cyclin‐dependent kinases and minichromosome maintenance protein in gastric cancer cells
Najar, M. A., Aravind, A., Dagamajalu, S., Sidransky, D., Ashktorab, H., Smoot, D. T., Gowda, H., Prasad, T. S. K., Modi, P. K., & Chatterjee, A. (2021) · Molecular Carcinogenesis · doi:10.1002/mc.23343 · Cited by 28
“Mitogen‐activated protein kinase (MAPK) pathways are conserved kinase modules that link extracellular signals to the machinery that controls fundamental cellular processes such as growth, proliferation, differentiation, migration, and apoptosis.(32) MAPK is one such complex interconnected signaling molecule with frequ…”
Background
ERK5 is involved in TCR‐induced apoptosis through the modification of Nur77
Fujii, Y., Matsuda, S., Takayama, G., & Koyasu, S. (2008) · Genes to Cells · doi:10.1111/j.1365-2443.2008.01177.x · Cited by 28
“In addition, MAPK is known to translocate into the nucleus once activated (Cobb & Goldsmith 1995; Schaeffer & Weber 1999 ).”
Background
Bcl-2 Up-Regulation and P-p53 Down-Regulation Account for the Low Sensitivity of Murine L929 Fibrosarcoma Cells to Oridonin-Induced Apoptosis
Huang, J. M., Li-jun, W., Tashiro, S., Onodera, S., & Ikejima, T. (2005) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.28.2068 · Cited by 28
Modeling specificity in the yeast MAPK signaling networks
Zou, X., Peng, T., & Pan, Z. (2007) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2007.09.024 · Cited by 28
“An important problem in cell biology is to understand how specificity from signals to cellular responses is maintained between different signal transduction pathways despite extensive interconnections and component sharing (Feng and Derynck, 2005; Hur and Kim, 2002; Marshall, 1995; Pawson, 2004; Tan and Kim, 1999; Sch…”
Background
Activation of Raf1 and the ERK pathway in response to l-ascorbic acid in acute myeloid leukemia cells
Park, S., Park, C. H., Hahm, E., Kım, K., Kimler, B. F., Lee, S. J., Park, H. K., Lee, S., Kim, W. S., Jung, C. W., et al. (2004) · Cellular Signalling · doi:10.1016/j.cellsig.2004.06.006 · Cited by 28
The mitogen-activated protein kinase Erk5 mediates human mesangial cell activation
Dorado, F., Velasco, S., Esparı́s-Ogando, A., Pericacho, M., Pandiella, A., Silva, J., López-Novoa, J. M., & Rodríguez‐Barbero, A. (2008) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gfn333 · Cited by 28
“Erk1/2 are activated primarily in response to proliferative stimuli [11,12], whereas the other MAPKs are activated primarily in response to inflammatory and stressful stimuli, including oxidant and osmotic stresses [13–15].”
Background
Protective Effect of Magnolol Against Hydrogen Peroxide-Induced Oxidative Stress in Human Lens Epithelial Cells
Yao, K., Zhang, L., Ye, P., Tang, X., & Zhang, Y.-D. (2009) · The American Journal of Chinese Medicine · doi:10.1142/s0192415x09007247 · Cited by 28
Adverse effects of MWCNTs on life parameters, antioxidant systems, and activation of MAPK signaling pathways in the copepod Paracyclopina nana
Kim, D., Puthumana, J., Kang, H.-M., Lee, M., Jeong, C., Han, J., Hwang, D., Kim, I., Lee, J. W., & Lee, J. (2016) · Aquatic Toxicology · doi:10.1016/j.aquatox.2016.08.016 · Cited by 28
Clinicopathological and prognostic significance of mitogen-activated protein kinases (MAPK) in breast cancers
Ahmad, D. A. J., Negm, O. H., Alabdullah, M. L., Mirza, S., Hamed, M. R., Band, V., Green, A. R., Ellis, I. O., & Rakha, E. A. (2016) · Breast Cancer Research and Treatment · doi:10.1007/s10549-016-3967-9 · Cited by 28
“For instance, ERK1/ERK2 is activated by MEK1 and MEK2, JNK is activated by MEK4 and MEK7 and p38 MAPK is activated by MEK3 and MEK6 [8, 9].”
Background
The Adaptogens Rhodiola and Schizandra Modify the Response to Immobilization Stress in Rabbits by Suppressing the Increase of Phosphorylated Stress-activated Protein Kinase, Nitric Oxide and Cortisol
Panossian, A. G., Hambardzumyan, M., Hovhanissyan, A., & Wikman, G. (2007) · Drug Target Insights · doi:10.33393/dti.2007.1309 · Cited by 28
Anti-apoptotic action of macrophage stimulating protein (MSP)
Danilkovitch‐Miagkova, A., & Leonard, E. J. (2001) · APOPTOSIS · doi:10.1023/a:1011384609811 · Cited by 28
Platelet-activating factor activates mitogen-activated protein kinases, inhibits proliferation, induces differentiation and suppresses the malignant phenotype of human colon carcinoma cells
Wang, H., & Chakrabarty, S. (2003) · Oncogene · doi:10.1038/sj.onc.1206348 · Cited by 28
“Since activation of MAP kinases has been reported in other cell types, we examined the effect of PAF on the activation of three prominent mammalian MAPK modules (Schaeffer and Weber, 1999).”
Background
Signaling pathways activated by vasoactive peptides in the cardiac myocyte and their role in myocardial pathologies
Sugden, P. H. (2002) · Journal of Cardiac Failure · doi:10.1054/jcaf.2002.129282 · Cited by 28
Diabetes modulates the expression of glomerular kinin receptors
Christopher, J., & Jaffa, A. A. (2002) · International Immunopharmacology · doi:10.1016/s1567-5769(02)00188-1 · Cited by 28
JIP1 regulates neuronal apoptosis in response to stress
Dong, Z., Zhou, L., Villar, K. D., Ghanevati, M., Tashjian, V. S., & Miller, C. A. (2005) · Molecular Brain Research · doi:10.1016/j.molbrainres.2004.10.039 · Cited by 28
Wavelength-specific Activation of MAP Kinase Family Proteins by Monochromatic UV Irradiation¶
Kabuyama, Y., Homma, M. K., Sekimata, M., & Homma, Y. (2001) · Photochemistry and Photobiology · doi:10.1562/0031-8655(2001)0730147wsaomk2.0.co2 · Cited by 28
Identification of a CD28 Response Element in the CD40 Ligand Promoter
Parra, E., Mustelin, T., Dohlsten, M., & Mercola, D. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.166.4.2437 · Cited by 28
Wiskott-Aldrich Syndrome Protein: Roles in Signal Transduction in T Cells
Ngoenkam, J., Paensuwan, P., Wipa, P., Schamel, W. W. A., & Pongcharoen, S. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.674572 · Cited by 28
“The activated Erk translocates to the nucleus and phosphorylates its substrate Elk1.”
BackgroundInfluential
Regulation of Hepatitis C virus replication and gene expression by the MAPK-ERK pathway
Pei, R., Zhang, X., Xu, S., Meng, Z., Roggendorf, M., Lu, M., & Chen, X. (2012) · Virologica Sinica · doi:10.1007/s12250-012-3257-6 · Cited by 27
“The activation of the MAPK-ERK pathway has a multiple effect on cellular processes([32]).”
Background
Ionizing radiation-induced gene modulations, cytokine content changes and telomere shortening in mouse fetuses exhibiting forelimb defects
Derradji, H., Bekaert, S., Meyer, T. D., Jacquet, P., Abou‐El‐Ardat, K., Ghardi, M., Michaux, A., & Baatout, S. (2008) · Developmental Biology · doi:10.1016/j.ydbio.2008.07.032 · Cited by 27
“It is involved in proliferation, senescence, differentiation and apoptosis (Kumar et al., 2004; Davis, 2000; Fanger, 1999; Schaeffer and Weber, 1999; Minden and Karin, 1997, Dent et al., 1999, 2003; Wang et al., 2000; Widmann et al., 1998; Rosette and Karin, 1996).”
Background
MEK/ERK pathway mediates insulin-promoted degradation of MKP-3 protein in liver cells
Feng, B., Jiao, P., Yang, Z., & Xu, H. (2012) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2012.03.025 · Cited by 28
“MAP kinases are important cellular mediators for transducting signals from a variety of extracellular stimuli (Chang and Karin, 2001; Schaeffer and Weber, 1999).”
Expression, Activity, and Regulation of MAP Kinases in Cultured Chondrocytes
Chun, J. (2004) · Humana Press eBooks · doi:10.1385/1-59259-810-2:291 · Cited by 27
miR-3188 Regulates Cell Proliferation, Apoptosis, and Migration in Breast Cancer by Targeting TUSC5 and Regulating the p38 MAPK Signaling Pathway
Chen, X., & Chen, J. (2017) · Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics · doi:10.3727/096504017x14953948675421 · Cited by 27
Retracted
Prosaptide TX14A stimulates growth, migration, and invasion and activates the Raf‐MEK‐ERK‐RSK‐Elk‐1 signaling pathway in prostate cancer cells
Koochekpour, S., Sartor, O. A., Lee, T., Zieske, A. W., Patten, D. Y., Hiraiwa, M., Sandhoff, K., Remmel, N., & Minokadeh, A. (2004) · The Prostate · doi:10.1002/pros.20082 · Cited by 27
“GPCRs use pathways that are similar to those utilized by receptor tyrosine kinases to activate the Raf/MEK/ERK cascade [25,26].”
The role of p38 MAP kinase and c-Jun N-terminal protein kinase signaling in the differentiation and apoptosis of immortalized neural stem cells
Yang, S., Cho, S., Ahn, N., Jung, J., Park, J., Jo, E., Hwang, J., Kim, S., Lee, B., Kang, K., et al. (2005) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/j.mrfmmm.2004.11.020 · Cited by 27
Identification of pY19-caveolin-2 as a positive regulator of insulin-stimulated actin cytoskeleton-dependent mitogenesis
Kwon, H., Jeong, K., & Pak, Y. (2008) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2008.00391.x · Cited by 27
Specificity Is Complex and Time Consuming: Mutual Exclusivity in Tyrosine Kinase-Mediated Signaling
O'Rourk, L., & Ladbury, J. E. (2003) · Accounts of Chemical Research · doi:10.1021/ar020167s · Cited by 27
Adenovirus vectors activate survival pathways in lung epithelial cells
Flaherty, D. M., Hinde, S. L., Monick, M. M., Powers, L. S., Bradford, M. A., Yarovinsky, T. O., & Hunninghake, G. W. (2004) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00359.2003 · Cited by 27
“Activated ERK can then translocate to the nucleus and alter the activity of a number of transcription factors involved in cytokine gene transcription and inhibition of apoptosis (4, 14, 53).”
Background
Regulation of Dual-specificity Phosphatases M3/6 and hVH5 by Phorbol Esters
Johnson, T. R., Biggs, J. R., Winbourn, S. E., & Kraft, A. S. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m004182200 · Cited by 27
Enteric neuroblasts require the phosphatidylinositol 3‐kinase pathway for GDNF‐stimulated proliferation
Focke, P. J., Schiltz, C. A., Jones, S. E., Watters, J. J., & Epstein, M. L. (2001) · Journal of Neurobiology · doi:10.1002/neu.1037 · Cited by 27
Leishmania mexicana amastigotes inhibit p38 and JNK and activate PI3K/AKT: role in the inhibition of apoptosis of dendritic cells
Vázquez-López, R., Argueta, J., Wilkins‐Rodríguez, A. A., Escalona‐Montaño, A. R., Aguirre‐García, M. M., & Gutiérrez‐Kobeh, L. (2015) · Parasite Immunology · doi:10.1111/pim.12275 · Cited by 26
Protein Arginine Methyltransferase 5 (PRMT5) Signaling Suppresses Protein Kinase Cδ- and p38δ-dependent Signaling and Keratinocyte Differentiation
Kanade, S. R., & Eckert, R. L. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.331660 · Cited by 26
Pro-Oncogenic and Anti-Oncogenic Pathways: Opportunities and Challenges of Cancer Therapy
Zhang, J., Chen, Y., & Lu, Q. (2010) · Future Oncology · doi:10.2217/fon.10.15 · Cited by 29
Antiestrogenic activity of flavonoid phytochemicals mediated via the c-Jun N-terminal protein kinase pathway. Cell-type specific regulation of estrogen receptor alpha
Collins‐Burow, B. M., Antoon, J. W., Frigo, D. E., Elliott, S. G., Weldon, C. B., Boué, S. M., Beckman, B. S., Curiel, T. J., Alam, J., McLachlan, J. A., et al. (2012) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2012.05.004 · Cited by 26

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
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
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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