Abstract
Sequential activation of protein kinases within the mitogen-activated protein kinase (MAPK) cascades is a common mechanism of signal transduction in many cellular processes. Four such cascades have been elucidated thus far, and named according to their MAPK tier component as the ERK1/2, JNK, p38MAPK, and ERK5 cascades. These cascades cooperate in transmitting various extracellular signals, and thus control cellular processes such as proliferation, differentiation, development, stress response, and apoptosis. Here we describe the classic ERK1/2 cascade, and concentrate mainly on the properties of MEK1/2 and ERK1/2, including their mode of regulation and their role in various cellular processes and in oncogenesis. This cascade may serve as a prototype of the other MAPK cascades, and the study of this cascade is likely to contribute to the understanding of mitogenic and other processes in many cell lines and tissues.
Similar content being viewed by others
References
Campbell, J. S., et al. (1995) The MAP kinase cascade. Recent Prog. Horm. Res. 50, 131–159.
Seger, R. and Krebs, E. G. (1995) The MAPK signaling cascade. FASEB J. 9, 726–735.
Chang, L. and Karin, M. (2001) Mammalian MAP kinase signalling cascades. Nature 410, 37–40.
Pearson, G., et al. (2001) Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocrinol. Rev. 22, 153–183.
Johnson, G. L. and Lapadat, R. (2002) Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 298, 1911–1912.
Bogoyevitch, M. A. and Court, N. W. (2004) Counting on mitogen-activated protein kinases—ERKs 3, 4, 5, 6, 7 and 8. Cell Signal 16, 1345–1354.
Canagarajah, B. J., et al. (1997) Activation mechanism of the MAP kinase ERK2 by dual phosphorylation. Cell 90, 859–869.
Payne, D. M., et al. (1991) Identification of the regulatory phosphorylation sites in pp42/mitogen activated protein kinase (MAP kinase). EMBO J. 10, 885–892.
Sturgill, T. W. and Ray, L. B. (1986) Muscle proteins related to microtubule associated protein-2 are substrates for an insulin-stimulatable kinase. Biochem. Biophys. Res. Commun. 134, 565–571.
Boulton, T. G., et al. (1991) ERKs: a family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF. Cell 65, 663–675.
Derijard, B., et al. (1994) JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell 76, 1025–1027.
Kyriakis, J. M., et al. (1994) The stress-activated protein kinase subfamily of c-Jun kinases. Nature 369, 156–160.
Freshney, N. W., et al. (1994) Interleukin-1 activates a novel protein kinase cascade that results in the phosphorylation of Hsp27. Cell 78, 1039–1049.
Han, J., et al. (1994) A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science 265, 808–811.
Rouse, J., et al. (1994) A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins. Cell 78, 1027–1037.
Zhou, G., et al. (1995) Components of a new human protein kinase signal transduction pathway. J. Biol. Chem. 270, 12665–12669.
Lee, J. D., et al. (1995) Primary structure of BMK1: a new mammalian map kinase. Biochem. Biophys. Res. Commun, 213, 715–724.
Bacus, S. S., et al. (2001) Taxol-induced apoptosis depends on MAP kinase pathways (ERK and p38) and is independent of p53. Oncogene 20, 147–155.
Hess, P., et al. (2002) Survival signaling mediated by c-Jun NH(2)-terminal kinase in transformed B lymphoblasts. Nat. Genet. 32, 201–205.
Zhang, W. and Liu, H. T. (2002) MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res. 12, 9–18.
Chang, F., et al. (2003) Regulation of cell cycle progression and apoptosis by the Ras/Raf/MEK/ERK pathway (Review). Int. J. Oncol. 22, 469–480.
Yao, Z. and Seger, R. (2004) The molecular mechanism of MAPK/ERK inactivation. Curr. Genomics 5, 385–393.
Chuderland, D. and Seger, R. (2005) Protein-protein interactions in the regulation of the extracellular signal-regulated kinase. Mol. Biotechnol. 29, 57–74.
Naor, Z., et al. (2000) Activation of MAPK cascades by G-protein-coupled receptors: the case of gonadotropin-releasing hormone receptor. Trends Endocrinol. Metab. 11, 91–99.
Marmor, M. D., et al. (2004) Signal transduction and oncogenesis by ErbB/HER receptors. Int. J. Radiat. Oncol. Biol. Phys. 58, 903–913.
Rane, S. G. (1999) Ion channels as physiological effectors for growth factor receptor and Ras/ERK signaling pathways. Adv. Second Messenger Phosphoprotein Res. 33, 107–127.
Wellbrock, C., et al. (2004) The RAF proteins take centre stage. Nat. Rev. Mol. Cell Biol. 5, 875–885.
Kolch, W., et al. (1993) Protein kinase C alpha activates RAF-1 by direct phosphorylation. Nature 364, 249–252.
Chadee, D. N. and Kyriakis, J. M. (2004) MLK3 is required for mitogen activation of B-Raf, ERK and cell proliferation. Nat. Cell Biol. 6, 770–776. Epub 2004 Jul 2018., 2004.
Barkoff, A., et al. (1998) Meiotic maturation in Xenopus requires polyadenylation of multiple mRNAs. EMBO J. 17, 3168–3175.
Alessi, D. R., et al. (1994) Identification of the sites in MAP kinase kinase-1 phosphorylated by p74raf-1. EMBO J. 13, 1610–1619.
Seger, R., et al. (1992) Purification and characterization of MAP kinase activator(s) from epidermal growth factor stimulated A431 cells. J. Biol. Chem. 267, 14373–14381.
Yung, Y., et al. (2000) ERK1b, a 46-kDa ERK isoform that is differentially regulated by MEK. J. Biol. Chem. 275, 15799–15808.
Aebersold, D. M., et al. (2004) Extracellular signal-regulated kinase 1c (ERK1c), a novel 42-kilodalton ERK, demonstrates unique modes of regulation, localization, and function. Mol. Cell Biol. 24, 10,000–10,015.
Lin, L. L., et al. (1993) cPLA2 is phosphorylated and activated by MAP kinase. Cell 72, 269–278.
Gille, H., et al. (1992) Phosphorylation of transcription factor p62TCF by MAP kinase stimulates ternary complex formation at c-fos promoter. Nature 358, 414–417.
Roux, P. P. and Blenis, J. (2004) ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiol. Mol. Biol. Rev. 68, 320–344.
Sturgill, T. W., et al. (1988) Insulin-stimulated MAP-2 kinase phosphorylates and activates ribosomal protein S6 kinase II. Nature 334, 715–718.
Deak, M., et al. (1998) Mitogen- and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB. EMBO J. 17, 4426–4441.
Fukunaga, R. and Hunter, T. (1997) MNK1, a new MAP kinase-activated protein kinase, isolated by a novel expression screening method for identifying protein kinase substrates. EMBO J. 16, 1921–1933.
Waskiewicz, A. J., et al. (1997) Mitogen-activated protein kinases activate the serine/threonine kinases Mnk1 and Mnk2. EMBO J. 16, 1909–1920.
Eldar-Finkelman, H., et al. (1995) Inactivation of glycogen synthase kinase-3 by epidermal growth factor is mediated by mitogen-activated protein kinase/p90 ribosomal protein S6 kinase signaling pathway in NIH/3T3 cells. J. Biol. Chem. 270, 987–990.
Sapkota, G. P., et al. (2001) Phosphorylation of the protein kinase mutated in Peutz-Jeghers cancer syndrome, LKB1/STK11, at Ser431 by p90RSK and cAMP-dependent protein kinase, but not its farnesylation at Cys433, is essential for LKB1 to suppress cell growth. J. Biol. Chem. 276, 19,469–19,482.
Uhlik, M. T., et al. (2004) Wiring diagrams of MAPK regulation by MEKK1, 2, and 3. Biochem. Cell Biol. 82, 658–663.
Han, J., et al. (1996) Characterization of the structure and function of a novel MAP kinase kinase (MKK6). J. Biol. Chem. 271, 2886–2891.
Derijard, B., et al. (1995) Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms [published erratum appears in Science 1995;269:17]. Science 267, 682–685.
Dashti, S. R., et al. (2001) MEK7-dependent activation of p38 MAP kinase in keratinocytes. J. Biol. Chem. 276, 8059–8063.
Ono, K. and Han, J. (2000) The p38 signal transduction pathway: activation and function. Cell Signal 12, 1–13.
Lee, J. C., et al. (1994) A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 372, 739–746.
Cuenda, A., et al. (1995) SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin-1. FEBS Lett. 364, 229–233.
Goedert, M., et al. (1997) Activation of the novel stress-activated protein kinase SAPK4 by cytokines and cellular stresses is mediated by SKK3 (MKK6); comparison of its substrate specificity with that of other SAP kinases. EMBO J. 16, 3563–3571.
Stokoe, D., et al. (1992) MAPKAP kinase-2; a novel protein kinase activated by mitogen-activated protein kinase. EMBO J. 11, 3985–3994.
McLaughlin, M. M., et al. (1996) Identification of mitogen-activated protein (MAP) kinase-activated protein kinase-3, a novel substrate of CSBP p38 MAP kinase. J. Biol. Chem. 271, 8488–8492.
New, L., et al. (1998) PRAK, a novel protein kinase regulated by the p38 MAP kinase. EMBO J. 17, 3372–3384.
Kramer, R. M., et al. (1996) p38 mitogen-activated protein kinase phosphorylates cytosolic phospholipase A2 (cPLA2) in thrombin-stimulated platelets. Evidence that proline-directed phosphorylation is not required for mobilization of arachidonic acid by cPLA2. J. Biol. Chem. 271, 27723–27729.
Ben-Levy, R., et al. (1998) Nuclear export of the stress-activated protein kinase p38 mediated by its substrate MAPKAP kinase-2. Curr. Biol. 8, 1049–1057.
Davis, R. J. (2000) Signal transduction by the JNK group of MAP kinases. Cell 103, 239–252.
Coso, O. A., et al. The small GTP-binding proteins Rac1 and Cdc42 regulate the activity of the JNK/SAPK signaling pathway. Cell 81, 1137–1146.
Dan, I., et al. (2001) The Ste20 group kinases as regulators of MAP kinase cascades. Trends Cell Biol. 11, 220–230.
Yan, M., et al. (1994) Activation of stress-activated protein kinase by MEKK1 phosphorylation of its activator SEK1. Nature 372, 798–800.
Tournier, C., et al. (1997) Mitogen-activated protein kinase kinase 7 is an activator of the c-Jun NH2-terminal kinase. Proc. Natl. Acad. Sci. USA 94, 7337–7342.
Holland, P. M., et al. (1997) MKK7 is a stress-activated mitogen-activated protein kinase kinase functionally related to hemipterous. J. Biol. Chem. 272, 24994–24998.
Hibi, M., et al. (1993) Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain. Genes & Dev. 7, 2135–2148.
Deng, X., et al. (2001) Novel role for JNK as a stress-activated Bcl2 kinase. J. Biol. Chem. 276, 25.
Zhang, Y., et al. (2001) UVA induces Ser381 phosphorylation of p90RSK/MAPKAP-K1 via ERK and JNK pathways. J. Biol. Chem. 276, 14,572–14,580.
Gdalyahu, A., et al. (2004) DCX, a new mediator of the JNK pathway. EMBO J. 23, 823–832.
Sun, W., et al. (2003) MEK kinase 2 and the adaptor protein Lad regulate extracellular signal-regulated kinase 5 activation by epidermal growth factor via Src. Mol. Cell Biol. 23, 2298–2308.
Abe, J., et al. (1997) c-Src is required for oxidative stress-mediated activation of big mitogen-activated protein kinase 1. J. Biol. Chem. 272, 20389–20394.
Xu, B. E., et al. (2004) WNK1 activates ERK5 by an MEKK2/3-dependent mechanism. J. Biol. Chem. 279, 7826–7831.
Camarillo, I. G., et al. (1997) Differential tyrosyl-phosphorylation of multiple mitogen-activated protein kinase isoforms in response to prolactin in Nb2 lymphoma cells. Proc. Soc. Exp. Biol. Med. 215, 198–202.
Chao, T. H., et al. (1999) MEKK3 directly regulates MEK5 activity as part of the big mitogen-activated protein kinase 1 (BMK1) signaling pathway. J. Biol. Chem. 274, 36035–36038.
Chayama, K., et al. (2001) Role of MEKK2-MEK5 in the regulation of TNF-alpha gene expression and MEKK2-MKK7 in the activation of c-Jun N-terminal kinase in mast cells. Proc. Natl. Acad. Sci. USA 98, 4599–4604.
Chiariello, M., et al. (2000) Multiple mitogen-activated protein kinase signaling pathways connect the cot oncoprotein to the c-jun promoter and to cellular transformation. Mol. Cell Biol. 20, 1747–1758.
Gotoh, I., et al. (2001) Identification and characterization of a novel MAP kinase kinase kinase, MLTK. J. Biol. Chem. 276, 4276–4286. Epub 2000 Oct 19, 2001.
English, J. M., et al. (1998) Identification of substrates and regulators of the mitogen-activated protein kinase ERK5 using chimeric protein kinases. J. Biol. Chem. 273, 3854–3860.
Yang, C. C., et al. (1998) Interaction of myocyte enhancer factor 2 (MEF2) with a mitogen-activated protein kinase, ERK5/BMK1. Nucleic Acids Res. 26, 4771–4777.
Kato, Y., et al. (1997) BMK1/ERK5 regulates serum-induced early gene expression through transcription factor MEF2C. EMBO J. 16, 7054–7066.
Kamakura, S., et al. (1999) Activation of the protein kinase ERK5/BMK1 by receptor tyrosine kinases. Identification and characterization of a signaling pathway to the nucleus. J. Biol. Chem. 274, 26,563–26,571.
Suzaki, Y., et al. (2002) Hydrogen peroxide stimulates c-Src-mediated big mitogen-activated protein kinase 1 (BMK1) and the MEF2C signaling pathway in PC12 cells: potential role in cell survival following oxidative insults. J. Biol. Chem. 277, 9614–9621.
Kasler, H. G., et al. (2000) ERK5 is a novel type of mitogen-activated protein kinase containing a transcriptional activation domain. Mol. Cell Biol. 20, 8382–8389.
Hayashi, M., et al. (2001) BMK1 mediates growth factor-induced cell proliferation through direct cellular activation of serum and glucocorticoid-inducible kinase. J. Biol. Chem. 276, 8631–8634.
Raviv, Z., et al. (2004) MEK5 and ERK5 are localized in the nuclei of resting as well as stimulated cells, while MEKK2 translocates from the cytosol to the nucleus upon stimulation. J. Cell Sci. 117, 1773–1784.
Buschbeck, M. and Ullrich, A. (2005) The unique C-terminal tail of the mitogen-activated protein kinase ERK5 regulates its activation and nuclear shuttling. J. Biol. Chem. 280, 2659–2667.
Kato, Y., et al. (1998) Bmk1/Erk5 is required for cell proliferation induced by epidermal growth factor. Nature 395, 713–716.
Kato, Y., et al. (2000) Role of BMK1 in regulation of growth factor-induced cellular responses. Immunol. Res. 21, 233–237.
Abe, M. K., et al. (1999) Extracellular signal-regulated kinase 7 (ERK7), a novel ERK with a C-terminal domain that regulates its activity, its cellular localization, and cell growth. Mol. Cell Biol. 19, 1301–1312.
Abe, M. K., et al. (2002) ERK8, a new member of the mitogen-activated protein kinase family. J. Biol. Chem. 277, 16733–16743.
Abe, M. K., et al. (2001) ERK7 is an autoactivated member of the MAP kinase family. J. Biol. Chem. 276, 3.
Boulton, T. G. and Cobb, M. H. (1991) Identification of multiple extracellular signal-regulated kinases (ERKs) with antipeptide antibodies. Cell Regul. 2, 357–371.
Lechner, C., et al. (1996) ERK6, a mitogen-activated protein kinase involved in C2C12 myoblast differentiation. Proc. Natl. Acad. Sci. U S A 93, 4355–4359.
Ferrell, J. E. Jr. (1996) Tripping the switch fantastic: how a protein kinase cascade can convert graded inputs into switch-like outputs. Trends Biochem. Sci. 21, 460–466.
Cowley, S., et al. (1994) Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells. Cell 77, 841–852.
Seger, R., et al. (1994) Over-expression of mitogen-activated protein kinase kinase (MAPKK) and its mutants in NIH-3T3 cells: evidence that MAPKK’s involvement in cellular proliferation is regulated by phosphorylation of serine residues in its kinase subdomains VII and VIII. J. Biol. Chem. 269, 25,699–25,709.
Zheng, C. F. and Guan, K. L. (1994) Activation of MEK family kinases requires phosphorylation of two conserved Ser/Thr residues. EMBO J. 13, 1123–1131.
Seger, R., et al. (1991) Microtubule-associated protein 2 kinases, ERK1 and ERK2, undergo autophosphorylation on both tyrosine and threonine residues: implication for their mechanism of activation. Proc. Natl. Acad. Sci. USA 88, 6142–6146.
Haystead, T. A., et al. (1992) Ordered phosphorylation of p42mapk by MAP kinase kinase. FEBS Lett. 306, 17–22.
Seger, R., et al. (1992) Human T-cell map kinase kinases are related to yeast signal transduction kinases. J. Biol. Chem. 267, 25,628–25,631.
Zheng, C. F. and Guan, K. L. (1993) Properties of MEKs, the kinases that phosphorylate and activate the extracellular signal-regulated kinases. J. Biol. Chem. 268, 23,933–23,939.
Sbendetz-Nezer, S. and Seger, R. (2005) The signaling Gateway, MEK2. AfCS/Nature, doi:10.1038/mp.a001506.01. ref info OK?
Resing, K.A., et al. (1995) Determination of v-Moscatalyzed phosphorylation sites and autophosphorylation sites on MAP kinase kinase by ESI/MS. Biochemistry 34, 2610–2620.
Eblen, S. T., et al. (2002) Rac-PAK signaling stimulates extracellular signal-regulated kinase (ERK) activation by regulating formation of MEK1-ERK complexes. Mol. Cell Biol. 22, 6023–6033.
Eblen, S. T., et al. (2004) Mitogen-activated protein kinase feedback phosphorylation regulates MEK1 complex formation and activation during cellular adhesion. Mol. Cell Biol. 24, 2308–2317.
Matsuda, S., et al. (1993) Phosphorylation of Xenopus mitogen-activated protein (MAP) kinase kinase by MAP kinase kinase kinase and MAP kinase. J. Biol. Chem. 268, 3277–3281.
Rossomando, A. J., et al. (1994) Mitogen-activated protein kinase kinase 1 (MKK1) is negatively regulated by threonine phosphorylation. Mcl. Cell Biol. 14, 1594–1602.
Crews, C. M., et al. (1992) The primary structure of MEK, a protein kinase that phosphorylates the ERK gene product. Science 258, 478–480.
Fukuda, M., et al. (1996) Cytoplasmic localization of mitogen-activated protein kinase kinase directed by its NH2-terminal, leucine-rich short amino acid sequence, which acts as a nuclear export signal. J. Biol. Chem. 271, 20,024–20,028.
Jaaro, H., et al. (1997) Nuclear translocation of mitogen-activated protein kinase kinase (MEK1) in response to mitogenic stimulation. Proc. Natl. Acad. Sci. USA 94, 3742–3747.
Tanoue, T., et al. (2000) A conserved docking motif in MAP kinases common to substrates, activators and regulators. Nat. Cell Biol. 2, 110–116.
Xu, B., et al. (1999) The N-terminal ERK-binding site of MEK1 is required for efficient feedback phosphorylation by ERK2 in vitro and ERK activation in vivo. J. Biol. Chem. 274, 34029–34035.
Dang, A., et al. (1998) The MEK1 proline-rich insert is required for efficient activation of the mitogen-activated protein kinases ERK1 and ERK2 in mammalian cells. J. Biol. Chem. 273, 19,909–19,913.
Cha, H., et al. (2001) Identification of a C-terminal region that regulates mitogen-activated protein kinase kinase-1 cytoplasmic localization and ERK activation. J. Biol. Chem. 276, 48494–48501.
Gonzalez, F. A., et al. (1992) Heterogeneous expression of four MAP kinase isoforms in human tissues. FEBS Lett. 304, 170–178.
Fukuda, M., et al. (1997) Interaction of MAP kinase with MAP kinase kinase: its possible role in the control of nucleocytoplasmic transport of MAP kinase. EMBO J. 16, 1901–1908.
Gonzalez, F. A., et al. (1991) Identification of substrate recognition determinants for human ERK1 and ERK2 protein kinases. J. Biol. Chem. 266, 22,159–22,163.
Haycock, J. W., et al. (1992) ERK1 and ERK2, two microtubule-associated protein 2 kinases, mediate the phosphorylation of tyrosine hydroxylase at serine-31 in situ. Proc. Natl. Acad. Sci. USA 89, 2365–2369.
Songyang, Z., et al. (1996) A structural basis for substrate specificities of protein Ser/Thr kinases: primary sequence preference of casein kinases I and II, NIMA, phosphorylase kinase, calmodulin-dependent kinase II, CDK5, and Erk1. Mol. Cell Biol. 16, 6486–6493.
Zhang, F., et al. (1994) Atomic structure of the MAP kinase ERK2 at 2.3 Å resolution. Nature 367, 704–711.
Wolf, I., et al. (2001) Involvement of the activation loop of ERK in the detachment from cytosolic anchoring. J. Biol. Chem. 276, 24,490–24,497.
Brunet, A. and Pouyssegur, J. (1996) Identification of MAP kinase domains by redirecting stress signals into growth factor responses. Science 272, 1652–1655.
Wilsbacher, J. L., et al. (1999) Phosphorylation of MAP kinases by MAP/ERK involves multiple regions of MAP kinases. J. Biol. Chem. 274, 16,988–16,994.
Eblen, S. T., et al. (2001) Biochemical and biological functions of the N-terminal, noncatalytic domain of extracellular signal-regulated kinase 2. Mol. Cell Biol. 21, 249–259.
Rubinfeld, H., et al. (1999) Identification of a cytoplasmic-retention sequence in ERK2. J. Biol. Chem. 274, 30349–30352.
Xu Be, B., et al. (2001) Hydrophobic as well as charged residues in both MEK1 and ERK2 are important for their proper docking. J. Biol. Chem. 276, 26509–26515.
Fukuda, M., et al. (1997) A novel regulatory mechanism in the mitogen-activated protein (MAP) kinase cascade. Role of nuclear export signal of MAP kinase kinase. J. Biol. Chem. 272, 32,642–32,648.
Bardwell, A. J., et al. (2001) A conserved docking site in MEKs mediates high-affinity binding to MAP kinases and cooperates with a scaffold protein to enhance signal transmission. J. Biol. Chem. 276, 10,374–10,386.
Bardwell, A. J., et al. (2003) Docking sites on mitogen-activated protein kinase (MAPK) kinases, MAPK phosphatases and the Elk-1 transcription factor compete for MAPK binding and are crucial for enzymic activity. Biochem. J. 370, 1077–1085.
Morrison, D. K. and Davis, R. J. Regulation of MAP kinase signaling modules by scaffold proteins in mammals. Annu. Rev. Cell Dev. Biol. 19, 91–118.
Zhang, J., et al. (2003) A bipartite mechanism for ERK2 recognition by its cognate regulators and substrates. J. Biol. Chem. 278, 29901–29912.
Yung, Y., et al. (2001) Altered regulation of ERK1b by MEK1 and PTP-SL, and modified Elk1 phosphorylation by ERK1b are caused by abrogation of the regulatory C-terminal sequence of ERKs. J. Biol. Chem. 276, 35280–35289.
Bott, C. M., et al. (1994) The sevenmaker gain-of-function mutation in p42 MAP kinase leads to enhanced signalling and reduced sensitivity to dual specificity phosphatase action. FEBS Lett. 352, 201–205.
Rohan, P. J., et al. (1993) PAC-1: a mitogen-induced nuclear protein tyrosine phosphatase. Science 259, 1763–1766.
Perlson, E., et al. (2005) Vimentin-dependent spatial translocation of an activated MAP kinase in injured nerve. Neuron 45, 715–726.
Volmat, V., et al. (2001) The nucleus, a site for signal termination by sequestration and inactivation of p42/p44 MAP kinases. J. Cell Sci. 114, 3433–3443.
Reszka, A. A., et al. (1995) Association of mitogen-activated protein kinase with the microtubule cytoskeleton. Proc. Natl. Acad. Sci. USA 92, 8881–8885.
Marshall, C. J. (1995) Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80, 179–185.
Keyse, S. M. (1998) Protein phosphatases and the regulation of MAP kinase activity. Semin. Cell Dev. Biol. 9, 143–152.
Chu, Y., et al. (1996) The mitogen-activated protein kinase phosphatases PAC1, MKP-1, and MKP-2 have unique substrate specificities and reduced activity in vivo toward the ERK2 sevenmaker mutation. J. Biol. Chem. 271, 6497–6501.
Muda, M., et al. (1996) The dual specificity phosphatases M3/6 and MKP-3 are highly selective for inactivation of distinct mitogen-activated protein kinases. J. Biol. Chem. 271, 27,205–27,208.
Camps, M., et al. (2000) Dual specificity phosphatases: a gene family for control of MAP kinase function. FASEB J. 14, 6–16.
Camps, M., et al. (1998) Induction of the mitogen-activated protein kinase phosphatase MKP3 by nerve growth factor in differentiating PC12. FEBS Lett. 425, 271–276.
Pulido, R., et al. (1998) PTP-SL and STEP protein tyrosine phosphatases regulate the activation of the extracellular signal-regulated kinases ERK1 and ERK2 by association through a kinase interaction motif. EMBO J. 17, 7337–7350.
Oh-hora, M., et al. (1999) Direct suppression of TCR-mediated activation of extracellular signal-regulated kinase by leukocyte protein tyrosine phosphatase, a tyrosine-specific phosphatase. J. Immunol. 163, 1282–1288.
Zuniga, A., et al. (1999) Interaction of mitogen-activated protein kinases with the kinase interaction motif of the tyrosine phosphatase PTP-SL provides substrate specificity and retains ERK2 in the cytoplasm. J. Biol. Chem. 274, 21,900–21,907.
Karim, F. D. and Rubin, G. M. (1999) PTP-ER, a novel tyrosine phosphatase, functions downstream of Ras1 to downregulate MAP kinase during Drosophila eye development. Mol. Cell 3, 741–750.
Yao, Z., et al. (2000) Detection of partially phosphorylated forms of ERK by monoclonal antibodies reveals spatial regulation of ERK activity by phosphatases. FEBS Lett. 468, 37–42.
Sontag, E., et al. (1993) The interaction of SV40 small tumor antigen with protein phosphatase 2A stimulates the map kinase pathway and induces cell proliferation. Cell 75, 887–897.
Buchwalter, G., et al. (2004) Ets ternary complex transcription factors. Gene 324, 1–14.
Cruzalegui, F. H., et al. (1999) ERK activation induces phosphorylation of Elk-1 at multiple S/T-P motifs to high stoichiometry. Oncogene 18, 7948–7957.
Cavigelli, M., et al. (1995) Induction of c-fos expression through JNK-mediated TCF/Elk-1 phosphorylation. EMBO J. 14, 5957–5964.
Marais, R., et al. (1993) The SRF accessory protein Elk-1 contains a growth factor-regulated transcriptional activation domain. Cell 73, 381–393.
Whitmarsh, A. J., et al. (1995) Integration of MAP kinase signal transduction pathways at the serum response element. Science 269, 403–407.
Murphy, L. O., et al. (2002) Molecular interpretation of ERK signal duration by immediate early gene products. Nat. Cell Biol. 4, 556–564.
Morton, S., et al. (2003) A reinvestigation of the multisite phosphorylation of the transcription factor c-Jun. EMBO J. 22, 3876–3886.
Jovanovic, J. N., et al. (1996) Neurotrophins stimulate phosphorylation of synapsin I by MAP kinase and regulate synapsin I-actin interactions. Proc. Natl. Acad. Sci. USA 93, 3679–3683.
Mitsushima, M., et al. (2004) Extracellular signal-regulated kinase activated by epidermal growth factor and cell adhesion interacts with and phosphorylates vinexin. J. Biol. Chem. 279, 34,570–34,577.
Ku, H. and Meier, K. E. (2000) Phosphorylation of paxillin via the ERK mitogen-activated protein kinase cascade in EL4 thymoma cells. J. Biol. Chem. 275, 11,333–11,340.
Northwood, I. C., et al. (1991) Isolation and characterization of two growth factor-stimulated protein kinases that phosphorylate the epidermal growth factor receptor at threonine 669. J. Biol. Chem. 266, 15,266–15,276.
Langlois, W. J., et al. (1995) Negative feedback regulation and desensitization of insulin- and epidermal growth factor-stimulated p2Iras activation. J. Biol. Chem. 270, 25,320–25,323.
Dougherty, M. K., et al. (2005) Regulation of Raf-1 by direct feedback phosphorylation. Mol. Cell 17, 215–224.
Peraldi, P., et al. (1993) Regulation of extracellular signal regulated protein kinase-1 (ERK1; pp44/mitogen-activated protein kinase) by epidermal growth factor and nerve growth factor in PC12 cells: implication of ERK1 inhibitory activities. Endocrinology 132, 2578–2585.
York, R. D., et al. Rap1 mediates sustained MAP kinase activation induced by nerve growth factor. Nature 392, 622–626.
Grewal, S. S., et al. (1999) Extracellular-signal-regulated kinase signalling in neurons. Curr. Opin. Neurobiol. 9, 544–553.
Hazan-Halevy, I., et al. (2000) The requirement of both extracellular regulated kinase and p38 mitogen-activated protein kinase for stimulation of cytosolic phospholipase A(2) activity by either FcgammaRIIA or FcgammaRIIIB in human neutrophils. A possible role for pyk2 but not for the grb2-sos-shc complex. J. Biol. Chem. 275, 12,416–12,423.
Elion, E. A. (2000) Pheromone response, mating and cell biology. Curr. Opin. Microbiol. 3, 573–581.
Schaeffer, H. J., et al. (1998) MP1: a MEK binding partner that enhances enzymatic activation of the MAP kinase cascade. Science 281, 1668–1671.
Yu, W., et al. (1998) Regulation of the MAP kinase pathway by mammalian Ksr through direct interaction with MEK and ERK. Curr. Biol. 8, 56–64.
Luttrell, L. M., et al. (2001) Activation and targeting of extracellular signal-regulated kinases by beta-arrestin scaffolds. Proc. Natl. Acad. Sci. USA 98, 2449–2454.
Ishibe, S., et al. (2004) Paxillin serves as an ERK-regulated scaffold for coordinating FAK and Rac activation in epithelial morphogenesis. Mol. Cell 16, 257–267.
Tournier, C., et al. (1999) The MKK7 gene encodes a group of c-Jun NH2-terminal kinase kinases. Mol. Cell Biol. 19, 1569–1581.
Sanz, V., et al. (2000) Distinct carboxy-termini confer divergent characteristics to the mitogen-activated protein kinase p38alpha and its splice isoform Mxi2. FEBS Lett. 474, 169–174.
Yan, C., et al. (2001) Molecular cloning of mouse ERK5/BMK1 splice variants and characterization of ERK5 functional domains. J. Biol. Chem. 276, 10,870–10,878.
Leevers, S. J., et al. (1994) Requirement for Ras in Raf activation is overcome by targeting Raf to the plasma membrane. Nature 369, 411–414.
Chen, R. H., et al. (1992) Nuclear localization and regulation of erk-and rsk-encoded protein kinases. Mol. Cell Biol. 12, 915–927.
Yung, Y., et al. (1997) Detection of ERK activation by a novel monoclonal antibody. FEBS Lett. 408, 292–296.
Lenormand, P., et al. (1993) Growth factors induce nuclear translocation of MAP kinases (p42mapk and p44mapk) but not of their activator MAP kinase kinase (p45mapkk) in fibroblasts. J. Cell Biol. 122, 1079–1088.
Tolwinski, N. S., et al. (1999) Nuclear localization of mitogen-activated protein kinase kinase 1 (MKK1) is promoted by serum stimulation and G2-M progression. Requirement for phosphorylation at the activation lip and signaling downstream of MKK. J. Biol. Chem. 274, 6168–6174.
Yao, Z., et al. (2001) Non-regulated and stimulated mechanisms cooperate in the nuclear accumulation of MEK1. Oncogene 20, 7588–7596.
Adachi, M., et al. (2000) Nuclear export of MAP kinase (ERK) involves a MAP kinase kinase (MEK)-dependent active transport mechanism [published erratum appears in J. Cell Biol. 2000;149:754]. J. Cell Biol. 148, 849–856.
Pouyssegur, J., et al. (2002) Fidelity and spatio-temporal control in MAP kinase (ERKs) signalling. Biochem. Pharmacol. 64, 755–763.
Whitehurst, A. W., et al. (2004) The death effector domain protein PEA-15 prevents nuclear entry of ERK2 by inhibiting required interactions. J. Biol. Chem. 5, 5.
Hunter, T. (1991) Cooperation between oncogenes. Cell 64, 249–270.
Sherr, C. J. (1996) Cancer cell cycle. Science 274, 1672–1677.
Kyriakis, J. M., et al. (1992) Raf-1 activates MAP kinase-kinase. Nature 358, 417–421.
Sun, H., et al. (1993) MKP-1 (3CH134), an immediate early gene product, is a dual specificity phosphatase that dephosphorylates MAP kinase in vivo. Cell 75, 487–493.
Pages, G., et al. (1993) Mitogen-activated protein kinases p42mapk and p44mapk are required for fibroblast proliferation. Proc. Natl. Acad. Sci. USA 90, 8319–8323.
Manser, E., et al. (1994) A brain serine/threonine protein kinase activated by Cdc42 and Rac1. Nature 367, 40–46.
Hoshino, R., et al. (1999) Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors. Oncogene 18, 813–822.
Sebolt-Leopold, J. S., et al. (1999) Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nat. Med. 5, 810–816.
Lavoie, J. N., et al. (1996) Cyclin D1 expression is regulated positively by the p42/p44MAPK and negatively by the p38/HOGMAPK pathway. J. Biol. Chem. 271, 20,608–20,616.
Woods, D., et al. (1997) Raf-induced proliferation or cell cycle arrest is determined by the level of Raf activity with arrest mediated by p21Cip1. Mol. Cell Biol. 17, 5598–5611.
Treinies, I., et al. (1999) Activated MEK stimulates expression of AP-1 components independently of phosphatidylinositol 3-kinase (PI3-kinase) but requires a PI3-kinase signal To stimulate DNA synthesis. Mol. Cell Biol. 19, 321–329.
Assoian, R. K. (2004) Stopping and going with p27kip1. Dev. Cell 6, 458–459.
Kawada, M., et al. (1997) Induction of p27Kip1 degradation and anchorage independence by Ras through the MAP kinase signaling pathway. Oncogene 15, 629–637.
Sewing, A., et al. (1997) High-intensity Raf signal causes cell cycle arrest mediated by p21Cip1. Mol. Cell Biol. 17, 5588–5597.
Serrano, M., et al. (1997) Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593–602.
Lloyd, A. C., et al. (1997) Cooperating oncogenes converge to regulate cyclin/cdk complexes. Genes & Dev. 11, 663–677.
Sidransky, D. and Hollstein, M. (1996) Clinical implications of the p53 gene. Annu. Rev. Med. 47, 285–301.
Lin, A. W., et al. (1998) Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Genes & Dev. 12, 3008–3019.
Zhu, J., et al. (1998) Senescence of human fibroblasts induced by oncogenic Raf. Genes & Dev. 12, 2997–3007.
Wright, J. H., et al. (1999) Mitogen-activated protein kinase kinase activity is required for the G(2)/M transition of the cell cycle in mammalian fibroblasts. Proc. Natl. Acad. Sci. U S A 96, 11335–11340.
Colanzi, A., et al. (2000) A specific activation of the mitogen-activated protein kinase kinase 1 (MEK1) is required for Golgi fragmentation during mitosis. J. Cell Biol. 149, 331–339.
Acharya, U., et al. (1998) Signaling via mitogen-activated protein kinase kinase (MEK1) is required for Golgi fragmentation during mitosis. Cell 92, 183–192.
Kharbanda, S., et al. (1994) Activation of Raf-1 and mitogen-activated protein kinases during monocytic differentiation of human myeloid leukemia cells. J. Biol. Chem. 269, 872–878.
Qiu, M. S. and Green, S. H. (1992) PC12 cell neuronal differentiation is associated with prolonged p21ras activity and consequent prolonged ERK activity. Neuron 9, 705–717.
Alberola-Ila, J., et al. (1995) Selective requirement for MAP kinase activation in thymocyte differentiation. Nature 373, 620–623.
Tsai, M., et al. (1993) Activation of MAP kinases, pp90rsk and pp70-S6 kinases in mouse mast cells by signaling through the c-kit receptor tyrosine kinase or Fc epsilon RI: rapamycin inhibits activation of pp70-S6 kinase and proliferation in mouse mast cells. Eur. J. Immunol. 23, 3286–3291.
Tsuda, L., et al. (1993) Protein kinase similar to MAP kinase activator acts downstream of the raf kinase in Drosophila. Cell 72, 407–414.
Gabay, L., et al. (1997) In situ activation pattern of Drosophila EGF receptor pathway during development. Science 277, 1103–1106.
Haccard, O., et al. (1993) Induction of metaphase arrest in cleaving Xenopus embryos by MAP kinase. Science 262, 1262–1265.
Katsura, I. (1993) In search of new mutants in cell-signaling systems of the nematode Caenorhabditis elegans. Genetica 88, 137–146.
Xia, Z., et al. (1995) Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 270, 1326–1331.
von Gise, A., et al. (2001) Apoptosis suppression by Raf-1 and MEK1 requires MEK- and phosphatidylinositol 3-kinase-dependent signals. Mol. Cell Biol. 21, 2324–2336.
Blagosklonny, M. V., et al. (1997) Raf-1/bcl-2 phosphorylation: a step from microtubule damage to cell death. Cancer Res. 57, 130–135.
Blazquez, C., et al. (2000) De novo-synthesized ceramide signals apoptosis in astrocytes via extracellular signal-regulated kinase. FASEB J. 14, 2315–2322.
Michael, D., et al. (1998) Repeated pulses of serotonin required for long-term facilitation activate mitogen-activated protein kinase in sensory neurons of Aplysia. Proc. Natl. Acad. Sci. USA 95, 1864–1869.
Berman, D. E., et al. (1998) Specific and differential activation of mitogen-activated protein kinase cascades by unfamiliar taste in the insular cortex of the behaving rat. J. Neurosci. 18, 10,037–10,044.
Pombo, C. M., et al. (1995) Activation of the SAPK pathway by the human STE20 homologue germinal centre kinase. Nature 377, 750–754.
Diener, K., et al. (1997) Activation of the c-Jun N-terminal kinase pathway by a novel protein kinase related to human germinal center kinase. Proc. Natl. Acad. Sci. USA 94, 9687–9692.
Shi, C. S. and Kehrl, J. H. (1997) Activation of stress-activated protein kinase/c-Jun N-terminal kinase, but not NF-kappaB, by the tumor necrosis factor (TNF) receptor 1 through a TNF receptor-associated factor-2 and germinal center kinase related-dependent pathway. J. Biol. Chem. 272, 32,102–32,107.
Kiefer, F., et al. (1996) HPK1, a hematopoietic protein kinase activating the SAPK/JNK pathway. EMBO J. 15, 7013–7025.
Yao, Z., et al. (1999) A novel human STE20-related protein kinase, HGK, that specifically activates the c-Jun N-terminal kinase signaling pathway. J. Biol. Chem. 274, 2118–2125.
Tung, R. M. and Blenis, J. (1997) A novel human SPS1/STE20 homologue, KHS, activates Jun N-terminal kinase. Oncogene 14, 653–659.
Sabourin, L. A. and Rudnicki, M. A. (1999) Induction of apoptosis by SLK, a Ste20-related kinase. Oncogene 18, 7566–7575.
Su, Y. C., et al. (1997) NIK is a new Ste20-related kinase that binds NCK and MEKK1 and activates the SAPK/JNK cascade via a conserved regulatory domain. EMBO J. 16, 1279–1290.
Johnston, A. M., et al. (2000) SPAK, a STE20/SPS1-related kinase that activates the p38 pathway. Oncogene 19, 4290–4297.
Graves, J. D., et al. (1998) Caspase-mediated activation and induction of apoptosis by the mammalian Ste20-like kinase Mst1. EMBO J. 17, 2224–2234.
Fu, C. A., et al. (1999) TNIK, a novel member of the germinal center kinase family that activates the c-Jun N-terminal kinase pathway and regulates the cytoskeleton. J. Biol. Chem. 274, 30,729–30,737.
Nakano, K., et al. (2000) NESK, a member of the germinal center kinase family that activates the c-Jun N-terminal kinase pathway and is expressed during the late stages of embryogenesis. J. Biol. Chem. 275, 20,533–20,539.
Dan, I., et al. (2000) Molecular cloning of MINK, a novel member of mammalian GCK family kinases, which is up-regulated during postnatal mouse cerebral development. FEBS Lett. 469, 19–23.
Zhang, S., et al. (1995) Rho family GTPases regulate p38 mitogen-activated protein kinase through the downstream mediator Pak 1. J. Biol. Chem. 270, 23,934–23,936.
Dan, C., et al. (2002) PAK5, a new brain-specific kinase, promotes neurite outgrowth in N1E-115 cells. Mol. Cell Biol. 22, 567–577.
Lin, J. L., et al. (2001) MST4, a new Ste20-related kinase that mediates cell growth and transformation via modulating ERK pathway. Oncogene 20, 6559–6569.
Ichijo, H., et al. (1997) Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science 275, 90–94.
Wang, X. S., et al. (1998) MAPKKK6, a novel mitogen-activated protein kinase kinase kinase, that associates with MAPKKK5. Biochem. Biophys. Res. Commun. 253, 33–37.
Yamaguchi, K., et al. (1995) Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transduction. Science 270, 2008–2011.
Sakuma, H., et al. (1997) Molecular cloning and functional expression of a cDNA encoding a new member of mixed lineage protein kinase from human brain. J. Biol. Chem. 272, 28,622–28,629.
Fan, G., et al. (1996) Dual leucine zipper-bearing kinase (DLK) activates p46SAPK and p38mapk but not ERK2. J. Biol. Chem. 271, 24,788–24,793.
Dorow, D. S., et al. (1993) Identification of a new family of human epithelial protein kinases containing two leucine/isoleucine-zipper domains. Eur. J. Biochem. 213, 701–710.
Dorow, D. S., et al. (1995) Complete nucleotide sequence, expression, and chromosomal localisation of human mixed-lineage kinase 2. Eur. J. Biochem. 234, 492–500.
Ing, Y. L., et al. (1994) MLK-3: identification of a widely-expressed protein kinase bearing an SH3 domain and a leucine zipper-basic region domain. Oncogene 9, 1745–1750.
Gallo, K. A. and Johnson, G. L. (2002) Mixed-lineage kinase control of JNK and p38 MAPK pathways. Nat. Rev. Mol. Cell Biol. 3, 663–672.
Liu, T. C., et al. (2000) Cloning and expression of ZAK, a mixed lineage kinase-like protein containing a leucine-zipper and a sterile-alpha motif. Biochem. Biophys. Res. Commun. 274, 811–816.
Lange-Carter, C. A., et al. (1993) A divergence in the MAP kinase regulatory network defined by MEK kinase and Raf. Science 260, 315–317.
Deacon, K. and Blank, J. L. (1997) Characterization of the mitogen-activated protein kinase kinase 4 (MKK4)/c-Jun NH2-terminal kinase 1 and MKK3/p38 pathways regulated by MEK kinases 2 and 3. MEK kinase 3 activates MKK3 but does not cause activation of p38 kinase in vivo. J. Biol. Chem. 272, 14,489–14,496.
Gerwins, P., et al. (1997) Cloning of a novel mitogen-activated protein kinase kinase kinase, MEKK4, that selectively regulates the c-Jun amino terminal kinase pathway. J. Biol. Chem. 272, 8288–8295.
Salmeron, A., et al. (1996) Activation of MEK-1 and SEK-1 by Tpl-2 proto-oncoprotein, a novel MAP kinase kinase kinase. EMBO J. 15, 817–826.
Peraldi, P., et al. (1995) Regulation of the MAP kinase cascade in PC12 cells: B-Raf activates MEK-1 (MAP kinase or ERK kinase) and is inhibited by cAMP. FEBS Lett. 357, 290–296.
Hagemann, C. and Rapp, U. R. (1999) Isotype-specific functions of Raf kinases. Exp. Cell Res. 253, 34–46.
Gotoh, Y. and Nishida, E. (1995) Activation mechanism and function of the MAP kinase cascade. Mol. Reprod. Dev. 42, 486–492.
Hutchison, M., et al. (1998) Isolation of TAO1, a protein kinase that activates MEKs in stress- activated protein kinase cascades [In Process Citation]. J. Biol. Chem. 273, 28625–28632.
Manning, G., et al. (2002) The protein kinase complement of the human genome. Science 298, 1912–1934.
Ahn, N. G., et al. (1991) Multiple components in an epidermal growth factor-stimulated protein kinase cascade. In vitro activation of myelin basic protein/microtubule-associated protein-2 kinase. J. Biol. Chem. 266, 4220–4227.
Ray, L. B. and Sturgill, T. W. (1987) Characterization of insulin-stimulated microtubule-associated protein kinase. Rapid isolation and stabilization of a novel serine/threonine kinase from 3T3-L1 cells. Proc. Natl. Acad. Sci. U S A 84, 1502–1506.
Ni, H., et al. (1998) MAPKAPK5, a novel mitogenactivated protein kinase (MAPK)-activated protein kinase, is a substrate of the extracellular-regulated kinase (ERK) and p38 kinase. Biochem. Biophys. Res. Commun. 243, 492–496.
Moore, T. M., et al. (2000) PSK, a novel STE20-like kinase derived from prostatic carcinoma that activates the c-Jun N-terminal kinase mitogen-activated protein kinase pathway and regulates actin cytoskeletal organization. J. Biol. Chem. 275, 4311–4322.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Rubinfeld, H., Seger, R. The ERK cascade. Mol Biotechnol 31, 151–174 (2005). https://doi.org/10.1385/MB:31:2:151
Issue Date:
DOI: https://doi.org/10.1385/MB:31:2:151