Fidelity and spatio-temporal control in MAP kinase (ERKs) signalling.

Extracellular signals transduced via receptor tyrosine kinases, G-protein-coupled receptors or integrins activate Ras, a key switch in cellular signalling. Although Ras can activate multiple downstream effectors (PI3K, Ral em leader ) one of the major activated pathway is a conserved sequential protein kinase cascade referred to as the mitogen activated protein (MAP) kinase module: Raf>MEK>ERK. The fidelity of signalling among protein kinases and the spatio-temporal activation are certainly key determinants for generating precise biological responses. The fidelity is ensured by scaffold proteins, a sort of protein kinase "insulators" and/or specific docking sites among the members of the signalling cascade. These docking sites are found in upstream and downstream regulators and MAPK substrates [Nat Cell Biol 2 2000 110]. The duration and the intensity of the response are in part controlled by the compartmentalisation of the signalling molecules. Growth factors promote nuclear accumulation and persistent activation of ERK (p42/p44 MAP kinases) during the entire G1 period with an extinction during S-phase. These features are exquisitely well controlled by (i) the temporal induction of the MAP kinase phosphatases, MKP1-3, and (ii) the compartmentalisation of the signalling molecules. We have shown that MKP1-2 induction is strictly controlled by the activation of the MAP kinase module providing evidence for an autoregulatory mechanism. This negative regulatory loop was further enhanced by the capacity of ERK to phosphorylate MKP1 and 2. This action reduced the degradation rate of these MKPs through the ubiquitin-proteasomal system [Science 286 1999 2514]. Whereas the two upstream kinases of the module, Raf and MEK remained cytoplasmic, ERK anchored to MEK in the cytoplasm of resting cells, rapidly translocated to the nucleus upon mitogenic stimulation. This process was rapid, reversible, and controlled by the strict activation of the MAPK cascade. Prevention of this nuclear translocation, by overexpression of a cytoplasmic ERK-docking molecule (inactive MKP3) prevented growth factor-stimulated DNA replication [EMBO J 18 1999 664]. Following long term stimulation, ERK progressively accumulated in the nucleus in an inactive form. This nuclear retention relied on the neosynthesis of short-lived nuclear anchoring proteins. Nuclear inactivation and sequestration was likely to be controlled by MAP kinase phosphatases 1 and 2. Therefore we propose that the nucleus represents a site for ERK action, sequestration and signal termination [J Cell Sci 114 2001 3433]. In addition, with the generation of mice invalidated for each of the ERK isoforms, we will illustrate that besides controlling cell proliferation the ERK cascade also controls cell differentiation and cell behaviour [Science 286 1999 1374].

[1]  G. Rubin,et al.  PTP-ER, a novel tyrosine phosphatase, functions downstream of Ras1 to downregulate MAP kinase during Drosophila eye development. , 1999, Molecular cell.

[2]  C. Widmann,et al.  Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human. , 1999, Physiological reviews.

[3]  R. Pulido,et al.  Two Clusters of Residues at the Docking Groove of Mitogen-activated Protein Kinases Differentially Mediate Their Functional Interaction with the Tyrosine Phosphatases PTP-SL and STEP* , 2002, The Journal of Biological Chemistry.

[4]  U. Rapp,et al.  The Ras-Raf relationship: an unfinished puzzle. , 2001, Advances in enzyme regulation.

[5]  J Downward,et al.  Interaction of Ras and Raf in intact mammalian cells upon extracellular stimulation. , 1994, The Journal of biological chemistry.

[6]  E. Nishida,et al.  Interaction of MAP kinase with MAP kinase kinase: its possible role in the control of nucleocytoplasmic transport of MAP kinase , 1997, The EMBO journal.

[7]  MAP kinases bite back. , 2001, Developmental cell.

[8]  A. Whitmarsh,et al.  The JNK-interacting Protein-1 Scaffold Protein Targets MAPK Phosphatase-7 to Dephosphorylate JNK* , 2003, The Journal of Biological Chemistry.

[9]  K Kornfeld,et al.  Docking Sites on Substrate Proteins Direct Extracellular Signal-regulated Kinase to Phosphorylate Specific Residues* , 2001, The Journal of Biological Chemistry.

[10]  N. Ahn,et al.  Signal transduction through MAP kinase cascades. , 1998, Advances in cancer research.

[11]  P. Cohen,et al.  Inactivation of p42 MAP kinase by protein phosphatase 2A and a protein tyrosine phosphatase, but not CL100, in various cell lines , 1995, Current Biology.

[12]  L. Bardwell,et al.  A conserved motif at the amino termini of MEKs might mediate high-affinity interaction with the cognate MAPKs. , 1996, Trends in biochemical sciences.

[13]  David P Wolfer,et al.  Knockout of ERK1 MAP Kinase Enhances Synaptic Plasticity in the Striatum and Facilitates Striatal-Mediated Learning and Memory , 2002, Neuron.

[14]  R. Lefkowitz,et al.  β-Arrestin Scaffolding of the ERK Cascade Enhances Cytosolic ERK Activity but Inhibits ERK-mediated Transcription following Angiotensin AT1a Receptor Stimulation* , 2002, The Journal of Biological Chemistry.

[15]  H. Schaeffer,et al.  MP1: a MEK binding partner that enhances enzymatic activation of the MAP kinase cascade. , 1998, Science.

[16]  N. Ahn,et al.  Distinct Cell Cycle Timing Requirements for Extracellular Signal-Regulated Kinase and Phosphoinositide 3-Kinase Signaling Pathways in Somatic Cell Mitosis , 2002, Molecular and Cellular Biology.

[17]  J. Pouysségur,et al.  A temporal and biochemical link between growth factor-activated MAP kinases, cyclin D1 induction and cell cycle entry. , 1996, Progress in cell cycle research.

[18]  A. Brunet,et al.  Nuclear translocation of p42/p44 mitogen‐activated protein kinase is required for growth factor‐induced gene expression and cell cycle entry , 1999, The EMBO journal.

[19]  M. Muda,et al.  Catalytic activation of the phosphatase MKP-3 by ERK2 mitogen-activated protein kinase. , 1998, Science.

[20]  J. Pouysségur,et al.  Cyclin D1 Expression Is Regulated Positively by the p42/p44MAPK and Negatively by the p38/HOGMAPK Pathway* , 1996, The Journal of Biological Chemistry.

[21]  J. Pouysségur,et al.  Defective thymocyte maturation in p44 MAP kinase (Erk 1) knockout mice. , 1999, Science.

[22]  K. Imai,et al.  Direct suppression of TCR-mediated activation of extracellular signal-regulated kinase by leukocyte protein tyrosine phosphatase, a tyrosine-specific phosphatase. , 1999, Journal of immunology.

[23]  J. Pouysségur,et al.  Pharmacological inhibitors of the ERK signaling pathway: application as anticancer drugs. , 2003, Progress in cell cycle research.

[24]  A. Pfeifer,et al.  A Novel 14-Kilodalton Protein Interacts with the Mitogen-Activated Protein Kinase Scaffold Mp1 on a Late Endosomal/Lysosomal Compartment , 2001, The Journal of cell biology.

[25]  E. Goldsmith,et al.  A constitutively active and nuclear form of the MAP kinase ERK2 is sufficient for neurite outgrowth and cell transformation , 1998, Current Biology.

[26]  M. Camps,et al.  The nucleus, a site for signal termination by sequestration and inactivation of p42/p44 MAP kinases. , 2001, Journal of cell science.

[27]  A. Whitmarsh,et al.  Signal transduction: A central control for cell growth , 2000, Nature.

[28]  Jonathan A. Cooper,et al.  Requirements for phosphorylation of MAP kinase during meiosis in Xenopus oocytes. , 1992, Science.

[29]  A. Sharrocks,et al.  The Elk-1 ETS-Domain Transcription Factor Contains a Mitogen-Activated Protein Kinase Targeting Motif , 1998, Molecular and Cellular Biology.

[30]  D. Morrison,et al.  C-TAK1 regulates Ras signaling by phosphorylating the MAPK scaffold, KSR1. , 2001, Molecular cell.

[31]  J. Pouysségur,et al.  The p42/p44 MAP kinase pathway prevents apoptosis induced by anchorage and serum removal. , 2000, Molecular biology of the cell.

[32]  J. Pouysségur,et al.  Spatiotemporal regulation of the p42/p44 MAPK pathway , 2001, Biology of the cell.

[33]  Roger J. Davis,et al.  The JIP Group of Mitogen-Activated Protein Kinase Scaffold Proteins , 1999, Molecular and Cellular Biology.

[34]  S. Baker,et al.  Nuclear import of activated D-ERK by DIM-7, an importin family member encoded by the gene moleskin. , 2001, Development.

[35]  E. Nishida,et al.  A conserved docking motif in MAP kinases common to substrates, activators and regulators , 2000, Nature Cell Biology.

[36]  E. Elion,et al.  Nuclear Shuttling of Yeast Scaffold Ste5 Is Required for Its Recruitment to the Plasma Membrane and Activation of the Mating MAPK Cascade , 1999, Cell.

[37]  M. Camps,et al.  Dual specificity phosphatases: a gene family for control of MAP kinase function , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[38]  E. Formstecher,et al.  PEA-15 mediates cytoplasmic sequestration of ERK MAP kinase. , 2001, Developmental cell.

[39]  E. Nishida,et al.  Evidence for Existence of a Nuclear Pore Complex-mediated, Cytosol-independent Pathway of Nuclear Translocation of ERK MAP Kinase in Permeabilized Cells* , 2001, The Journal of Biological Chemistry.

[40]  A. Brunet,et al.  Growth factors induce nuclear translocation of MAP kinases (p42mapk and p44mapk) but not of their activator MAP kinase kinase (p45mapkk) in fibroblasts , 1993, The Journal of cell biology.

[41]  Matthias Peter,et al.  MAP kinase dynamics in response to pheromones in budding yeast , 2001, Nature Cell Biology.

[42]  E. Nishida,et al.  Two co‐existing mechanisms for nuclear import of MAP kinase: passive diffusion of a monomer and active transport of a dimer , 1999, The EMBO journal.

[43]  J. Pouysségur,et al.  Mitogen-activated protein kinases p42mapk and p44mapk are required for fibroblast proliferation. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[44]  E. Nishida,et al.  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* , 1996, The Journal of Biological Chemistry.

[45]  E. Goldsmith,et al.  Phosphorylation of the MAP Kinase ERK2 Promotes Its Homodimerization and Nuclear Translocation , 1998, Cell.

[46]  J. Pouysségur,et al.  Reduced MAP kinase phosphatase-1 degradation after p42/p44MAPK-dependent phosphorylation. , 1999, Science.

[47]  E. Nishida,et al.  Nuclear Export of Map Kinase (ERK) Involves a Map Kinase Kinase (Mek-Dependent) Active Transport Mechanism , 2000, The Journal of cell biology.

[48]  E. Nishida,et al.  Identification of a docking groove on ERK and p38 MAP kinases that regulates the specificity of docking interactions , 2001, The EMBO journal.

[49]  P. Cohen,et al.  EGF triggers neuronal differentiation of PC12 cells that overexpress the EGF receptor , 1994, Current Biology.

[50]  J. Pouysségur,et al.  Coordinate, biphasic activation of p44 mitogen-activated protein kinase and S6 kinase by growth factors in hamster fibroblasts. Evidence for thrombin-induced signals different from phosphoinositide turnover and adenylylcyclase inhibition. , 1992, The Journal of biological chemistry.

[51]  Philippe P Roux,et al.  Raf-MEK-Erk Cascade in Anoikis Is Controlled by Rac1 and Cdc42 via Akt , 2001, Molecular and Cellular Biology.

[52]  J E Ferrell,et al.  Distinct, constitutively active MAPK phosphatases function in Xenopus oocytes: implications for p42 MAPK regulation In vivo. , 1999, Molecular biology of the cell.

[53]  D. Carrasco,et al.  Disruption of the erp/mkp-1 gene does not affect mouse development: normal MAP kinase activity in ERP/MKP-1-deficient fibroblasts. , 1996, Oncogene.

[54]  S. Keyse,et al.  Protein phosphatases and the regulation of mitogen-activated protein kinase signalling. , 2000, Current opinion in cell biology.

[55]  E. Elion,et al.  Ste5: a meeting place for MAP kinases and their associates. , 1995, Trends in cell biology.

[56]  A. Brunet,et al.  Growth Factor–induced p42/p44 MAPK Nuclear Translocation and Retention Requires Both MAPK Activation and Neosynthesis of Nuclear Anchoring Proteins , 1998, The Journal of cell biology.

[57]  D. Teis,et al.  Localization of the MP1-MAPK scaffold complex to endosomes is mediated by p14 and required for signal transduction. , 2002, Developmental cell.

[58]  J. Pouysségur,et al.  The Dual Specificity Mitogen-activated Protein Kinase Phosphatase-1 and −2 Are Induced by the p42/p44MAPK Cascade* , 1997, The Journal of Biological Chemistry.

[59]  R. Herbst,et al.  The MAP-kinase ERK2 is a specific substrate of the protein tyrosine phosphatase HePTP , 2000, Oncogene.

[60]  A. Sharrocks,et al.  Docking domains and substrate-specificity determination for MAP kinases. , 2000, Trends in biochemical sciences.

[61]  M. Gabrielsen,et al.  Distinct Binding Determinants for ERK2/p38α and JNK MAP Kinases Mediate Catalytic Activation and Substrate Selectivity of MAP Kinase Phosphatase-1* 210 , 2001, The Journal of Biological Chemistry.

[62]  D. Morrison,et al.  KSR: a MAPK scaffold of the Ras pathway? , 2001, Journal of cell science.

[63]  M. Therrien,et al.  KSR is a scaffold required for activation of the ERK/MAPK module. , 2002, Genes & development.

[64]  R. Davis,et al.  Structural organization of MAP-kinase signaling modules by scaffold proteins in yeast and mammals. , 1998, Trends in biochemical sciences.