Cited by 1,555Protein Kinase Regulation and GTPase SignalingMelanoma and MAPK PathwaysProtein Tyrosine Phosphatases

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Independent Human MAP-Kinase Signal Transduction Pathways Defined by MEK and MKK Isoforms

Dérijard, Benoit, Raingeaud, Joël, Barrett, Tamera, Wu, I-Huan, Han, Jiahuai, Ulevitch, Richard J., Davis, Roger J.·1995·Science

DOI 10.1126/science.7839144

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Abstract

Mammalian mitogen-activated protein (MAP) kinases include extracellular signal-regulated protein kinase (ERK), c-Jun amino-terminal kinase (JNK), and p38 subgroups. These MAP kinase isoforms are activated by dual phosphorylation on threonine and tyrosine. Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase. These MKK isoforms did not activate the ERK subgroup of MAP kinases, but MKK4 did activate JNK. These data demonstrate that the activators of p38 (MKK3 and MKK4), JNK (MKK4), and ERK (MEK1 and MEK2) define independent MAP kinase signal transduction pathways.

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Background
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Background
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Background
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Background
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Background
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Self-citation
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Crystal structures of MKK4 kinase domain reveal that substrate peptide binds to an allosteric site and induces an auto-inhibition state
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Biological Properties of JNK3 and Its Function in Neurons, Astrocytes, Pancreatic β-Cells and Cardiovascular Cells
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“MKK4 and MKK7 reportedly induce the activation of JNK via dual phosphorylation of Tyr and Thr residues [10,11].”
Background
Modulation of p53 by mitogen-activated protein kinase pathways and protein kinase C δ during avian reovirus S1133-induced apoptosis
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Role of β-Catenin in Post-Meiotic Male Germ Cell Differentiation
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“Gene expression analyses revealed that b-catenin deletion resulted in elevated expression of Map2k7 (MKK7) and Mapkapk2 (MK2) (Table S2 and Figure 6A), which may be directly involved in actin restructuring and adherens junction kinetics by activating downstream JNK and p38 MAPK (Figure 6B) [37,38,39,40,41,42,43,44,45,…”
Background
G protein–coupled receptors activate p38 MAPK via a non-canonical TAB1–TAB2– and TAB1–TAB3–dependent pathway in endothelial cells
Grimsey, N. J., Lin, Y., Narala, R., Rada, C. C., Mejia-Pena, H., & Trejo, J. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.007495 · Cited by 51
“Although MKK3 and MKK6 are the major upstream MAP2Ks for p38 activation in response to cytokines or stress (40, 41), we found that multiple GPCR agonists failed to induce consistent and robust phosphorylation of MKK3 or MKK6 in distinct endothelial cell types compared with VEGF.”
Background
Phorbol myristate acetate transactivates the avian β3 integrin gene and induces αvβ3 integrin expression
Zhu, H.-J., Ross, F. P., Cao, X., & Teitelbaum, S. L. (1996) · Journal of Cellular Biochemistry · doi:10.1002/(sici)1097-4644(19960601)61:3 · Cited by 6
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“Is the ERK pathway the only MAP kinase pathway that can regulate TCF activity? At least two other MAP kinase pathways are present in mammalian cells, controlling activity of the JNK/SAPKs and p38/RK (for references see Han et al. 1994; Rouse et al. 1994; Sanchez et al. 1994; Yan et al. 1994; Derijard et al. 1995).”
Background
Involvement of p38 Mitogen-activated Protein Kinase Signaling Pathway in the Rapid Induction of the 78-kDa Glucose-regulated Protein in 9L Rat Brain Tumor Cells
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Activation of Multiple Mitogen-activated Protein Kinase Signal Transduction Pathways by the Endothelin B Receptor Requires the Cytoplasmic Tail
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Carbon Monoxide Releasing Molecule-2 Inhibits Pancreatic Stellate Cell Proliferation by Activating p38 Mitogen-Activated Protein Kinase/Heme Oxygenase-1 Signaling
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“5B) and JNK (Fig.”
BackgroundInfluential
MEK6 Regulates Human Involucrin Gene Expression via a p38α- and p38δ-dependent Mechanism
Dashti, S. R., Efimova, T., & Eckert, R. L. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m100465200 · Cited by 47
Hypotonicity stimulates renal epithelial sodium transport by activating JNK via receptor tyrosine kinases
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“In turn, MEKK1 phosphorylates and activates the MAPK kinase MKK4, which activates JNK/SAPK (13, 44).”
Background
Differential activation of mitogen‐activated protein kinase signalling pathways by isometric contractions in isolated slow‐ and fast‐twitch rat skeletal muscle
Wretman, Widegren, Lionikas, Westerblad, H., & Henriksson, J. (2000) · Acta Physiologica Scandinavica · doi:10.1046/j.1365-201x.2000.00752.x · Cited by 47
Vasoactive intestinal peptide and pituitary adenylate cyclase activating polypeptide inhibit the MEKK1/MEK4/JNK signaling pathway in LPS-stimulated macrophages
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Activation of RSK by UV-light: phosphorylation dynamics and involvement of the MAPK pathway
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“…at least two stress-activated protein kinase (SAPK) pathways exist, the MAPK/Jun N-terminal protein kinase (JNK) (Cano and Mahadevan, 1995; Mohit et al., 1995; Lin et al., 1995; Derijard et al., 1995) and the MAPK/p38 (Freshney et al., 1994; Han et al., 1994; Lee et al., 1994; Rouse et al., 1994).”
Background
Differential Activation of Two JNK Activators, MKK7 and SEK1, by MKN28-derived Nonreceptor Serine/Threonine Kinase/Mixed Lineage Kinase 2
Hirai, S.-I., Nöda, K., Moriguchi, T., Nishida, E., Yamashita, A., Deyama, T., Fukuyama, K., & Ohno, S. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.13.7406 · Cited by 47
src‐related tyrosine kinases regulate transcriptional activation of the interstitial collagenase gene, MMP‐1, in interleukin‐1‐stimulated synovial fibroblasts
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Distinct Role of p38 and c-Jun N-Terminal Kinases in IL-10-Dependent and IL-10-Independent Regulation of the Costimulatory Molecule B7.2 in Lipopolysaccharide-Stimulated Human Monocytic Cells
Lim, W., Ma, W., Gee, K., Aucoin, S., Nandan, D., Díaz‐Mitoma, F., Kozlowski, M., & Kumar, A. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.168.4.1759 · Cited by 46
“However, it has been shown recently that MKK4 can also activate the p38 MAPK (54, 56).”
Background
p38 mitogen‐activated protein kinase dephosphorylation is regulated by protein phosphatase 2A in human platelets activated by collagen
Sundaresan, P., & Farndale, R. W. (2002) · FEBS Letters · doi:10.1016/s0014-5793(02)03277-5 · Cited by 46
Newer Immunosuppressive Drugs
Drosos, A. A. (2002) · Drugs · doi:10.2165/00003495-200262060-00003 · Cited by 46
“include an increase in the T cell stimulatory capacity and expression of cell surface molecules, as well as the suppressive effect of endocytosis and chemotactic migration.[8,11,18] 3.”
BackgroundInfluential
MAPK p38α Is Dispensable for Lymphocyte Development and Proliferation
Kim, J. M., White, J. M., Shaw, A. S., & Sleckman, B. P. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.3.1239 · Cited by 46
“The activity of the p38 MAPKs is regulated by MKK3, MKK4, and MKK6 (7, 8, 20, 21).”
Background
p38α Isoform Mxi2 Binds to Extracellular Signal-Regulated Kinase 1 and 2 Mitogen-Activated Protein Kinase and Regulates Its Nuclear Activity by Sustaining Its Phosphorylation Levels
Sanz‐Moreno, V., Casar, B., & Crespo, P. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.9.3079-3090.2003 · Cited by 45
Synergistic Activation of NF-κB by Functional Cooperation between Vav and PKCθ in T Lymphocytes
Dienz, O., Hehner, S. P., Dröge, W., & Schmitz, M. L. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.c000177200 · Cited by 46
Gα16 Mimics Vasoconstrictor Action to Induce Smooth Muscle α-Actin in Vascular Smooth Muscle Cells through a Jun-NH2-terminal Kinase-dependent Pathway
Higashita, R., Li, L., Putten, V. V., Yamamura, Y., Zarinetchi, F., Heasley, L. E., & Nemenoff, R. A. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.41.25845 · Cited by 46
Thrombin-Induced Connective Tissue Growth Factor Expression in Human Lung Fibroblasts Requires the ASK1/JNK/AP-1 Pathway
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“JNKs are activated after their dual phosphorylation of threonine and tyrosine by the specific MKK4 and MKK7 (44, 45).”
Background
Modulating sensitivity to drug-induced apoptosis: the future for chemotherapy?
Makin, G., & Dive, C. (2001) · Breast Cancer Research · doi:10.1186/bcr289 · Cited by 45
“In the ERK1/ERK2 module, growth factor derived extracellular signals are translated to Raf-1 activation, which leads to the phosphorylation of MAP kinase kinase (MEK)1 and MEK2; these in turn phosphorylate and activate ERK1 and ERK2.”
Influential
All three IκB isoforms and most Rel family members are stably associated with the IκB kinase 1/2 complex
Heilker, R., Freuler, F., Pulfer, R., Padova, F. D., & Eder, J. (1999) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.1999.00028.x · Cited by 45
p38 MAP kinase modulates liver cell volume through inhibition of membrane Na+ permeability
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Self-citation
Phorbol Ester-induced Expression of Airway Squamous Cell Differentiation Marker, SPRR1B, Is Regulated by Protein Kinase Cδ/Ras/MEKK1/MKK1-dependent/AP-1 Signal Transduction Pathway
Vuong, H., Patterson, T., Shapiro, P. S., Kalvakolanu, D. V., Wu, R., Ma, W.-Y., Dong, Z., Kleeberger, S. R., & Reddy, S. P. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m005227200 · Cited by 45
Analyzing JNK and p38 mitogen-activated protein kinase activity
Whitmarsh, A. J., & Davis, R. J. (2001) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(01)32212-7 · Cited by 45
Self-citation
Radiation-Induced Apoptosis: The Ceramide-SAPK Signaling Pathway and Clinical Aspects
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p38 MAP kinase negatively regulates cyclin D1 expression in airway smooth muscle cells
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“p38a was originally identified in lipopolysaccharidestimulated mouse macrophages and was found to have substantial homology to the yeast high-osmolarity glycerol kinase (9, 18, 36, 38).”
Background
Signal Transduction Pathways Activated by CpG-DNA
Häcker, H. (2000) · Current topics in microbiology and immunology · doi:10.1007/978-3-642-59672-8_5 · Cited by 45
Induction of p21/WAF1 and G1 cell-cycle arrest by the chemopreventive agent apigenin
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Heat Shock Protein B1-Deficient Mice Display Impaired Wound Healing
Crowe, J., Aubareda, A., McNamee, K., Przybycien-Gaweda, P. M., Lü, X., Williams, R. O., Bou–Gharios, G., Saklatvala, J., & Dean, J. L. E. (2013) · PLoS ONE · doi:10.1371/journal.pone.0077383 · Cited by 44
“The pathway comprises the upstream activator, TGF-b-activated protein kinase [24], MAPK kinases-3 and -6 [25,26], p38 MAPK itself, MAPK-activated protein kinase-2 [22,23], and various downstream substrates including the RNA-”
Background

Authors: Dérijard, B., Raingeaud, J., Barrett, T., Wu, I.-H., Han, J., Ulevitch, R. J., & Davis, R. J.
Affiliations: University of Massachusetts Chan Medical School (US)
ORCID: Han, Jiahuai
Ulevitch, Richard J.
Davis, Roger J.
Venue: Science
Publisher: American Association for the Advancement of Science (AAAS)
Published: 1995-02-03
Volume: 267
Issue: 5198
Pages: 682-685
ISSN: 0036-8075 (ISSN-L)
1095-9203
DOI: 10.1126/science.7839144
OpenAlex: W1998487776
Cited by: 1,555
References: 29
Citations by year: 2026: 8 · 2025: 9 · 2024: 9 · 2023: 12 · 2022: 16 · 2021: 19 · 2020: 14 · 2019: 20 · 2018: 16 · 2017: 19 · 2016: 24 · 2015: 15 · 2014: 27 · 2013: 25 · 2012: 27
FWCI: 53.10
Type: journal article
Language: en
Open access: closed
Locations: Science (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (5r01ca058396-09)
National Cancer Institute (CA 58396)
National Institute of General Medical Sciences (GM 37696, P01GM037696)
National Institute of Allergy and Infectious Diseases (AI 15136, R01AI015136)
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: MAPK signaling, MKK3, MKK4, p38 MAPK, ERK, JNK, signaling pathways, dual phosphorylation
MeSH terms: Amino Acid Sequence, Animals, Base Sequence, Cell Line, Cloning, Molecular, Enzyme Activation, Humans, Molecular Sequence Data, Phosphorylation, Protein-Tyrosine Kinases, Substrate Specificity, Transfection, Signal Transduction, Protein Serine-Threonine Kinases, Calcium-Calmodulin-Dependent Protein Kinases, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase Kinases, JNK Mitogen-Activated Protein Kinases, p38 Mitogen-Activated Protein Kinases, MAP Kinase Kinase 3, MAP Kinase Kinase 4

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Independent Human MAP-Kinase Signal Transduction Pathways Defined by MEK and MKK Isoforms

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