BBA - Molecular Cell Research (v.1773, #8)

MAP kinase pathways: The first twenty years by Joseph Avruch (1150-1160).
The MAP kinases, discovered approximately 20 years ago, together with their immediate upstream regulators, are among the most highly studied signal transduction molecules. This body of work has shaped many aspects of our present views of signal transduction by protein kinases. The effort expended in this area reflects the extensive participation of these regulatory modules in the control of cell fate decisions, i.e., proliferation, differentiation and death, across all eukaryotic phylla and in all tissues of metazoans. The discovery of these kinases is reviewed, followed by a discussion of some of the features of this signaling module that account for its broad impact on cell function and its enormous interest to many investigators.
Keywords: MAP kinase; ERK; JNK; p38; SAPK; Protein phosphorylation; Protein kinase cascade; Signal transduction; Docking site; Scaffold protein; Transcriptional regulation; Cell fate;

Regulation of MAPKs by growth factors and receptor tyrosine kinases by Menachem Katz; Ido Amit; Yosef Yarden (1161-1176).
Multiple growth- and differentiation-inducing polypeptide factors bind to and activate transmembrane receptors tyrosine kinases (RTKs), to instigate a plethora of biochemical cascades culminating in regulation of cell fate. We concentrate on the four linear mitogen-activated protein kinase (MAPK) cascades, and highlight organizational and functional features relevant to their action downstream to RTKs. Two cellular outcomes of growth factor action, namely proliferation and migration, are critically regulated by MAPKs and we detail the underlying molecular mechanisms. Hyperactivation of MAPKs, primarily the Erk pathway, is a landmark of cancer. We describe the many links of MAPKs to tumor biology and review studies that identified machineries permitting prolongation of MAPK signaling. Models attributing signal integration to both phosphorylation of MAPK substrates and to MAPK-regulated gene expression may shed light on the remarkably diversified functions of MAPKs acting downstream to activated RTKs.
Keywords: Cancer; Growth factor; Signal transduction; Transcription; Tyrosine kinase;

Ras oncogenes and their downstream targets by Krishnaraj Rajalingam; Ralf Schreck; Ulf R. Rapp; Štefan Albert (1177-1195).
RAS proteins are small GTPases, which serve as master regulators of a myriad of signaling cascades involved in highly diverse cellular processes. RAS oncogenes have been originally discovered as retroviral oncogenes, and ever since constitutively activating RAS mutations have been identified in human tumors, they are in the focus of intense research. In this review, we summarize the biochemical properties of RAS proteins, trace down the evolution of RAS signaling and present an overview of the spatio-temporal activation of major RAS isoforms. We further discuss RAS effector pathways, their role in normal and transformed cell physiology and summarize ongoing attempts to interfere with aberrant RAS signaling. Finally, we comment on the role of micro RNAs in modulating RAS expression, contribution of RAS to stem cell function and on high-throughput analyses of RAS signaling networks.
Keywords: RAS; Small GTPases; RAS effector pathways; Mitogenic cascade; Oncogenic signaling; Mutational activation;

Raf kinases: Function, regulation and role in human cancer by Deborah T. Leicht; Vitaly Balan; Alexander Kaplun; Vinita Singh-Gupta; Ludmila Kaplun; Melissa Dobson; Guri Tzivion (1196-1212).
The Ras-Raf-MAPK pathway regulates diverse physiological processes by transmitting signals from membrane based receptors to various nuclear, cytoplasmic and membrane-bound targets, coordinating a large variety of cellular responses. Function of Raf family kinases has been shown to play a role during organism development, cell cycle regulation, cell proliferation and differentiation, cell survival and apoptosis and many other cellular and physiological processes. Aberrations along the Ras-Raf-MAPK pathway play an integral role in various biological processes concerning human health and disease. Overexpression or activation of the pathway components is a common indicator in proliferative diseases such as cancer and contributes to tumor initiation, progression and metastasis. In this review, we focus on the physiological roles of Raf kinases in normal and disease conditions, specifically cancer, and the current thoughts on Raf regulation.
Keywords: Raf; Phosphorylation; Cancer; MAPK; Ras;

The ERK signaling cascade is a central MAPK pathway that plays a role in the regulation of various cellular processes such as proliferation, differentiation, development, learning, survival and, under some conditions, also apoptosis. The ability of this cascade to regulate so many distinct, and even opposing, cellular processes, raises the question of signaling specificity determination by this cascade. Here we describe mechanisms that cooperate to direct MEK-ERK signals to their appropriate downstream destinations. These include duration and strength of the signals, interaction with specific scaffolds, changes in subcellular localization, crosstalk with other signaling pathways, and presence of multiple components with distinct functions in each tier of the cascade. Since many of the mechanisms do not function properly in cancer cells, understanding them may shed light not only on the regulation of normal cell proliferation, but also on mechanisms of oncogenic transformation.
Keywords: MAPK; ERK; MEK; Signaling specificity;

Regulation of MAP kinases by MAP kinase phosphatases by Kunio Kondoh; Eisuke Nishida (1227-1237).
MAP kinase phosphatases (MKPs) catalyze dephosphorylation of activated MAP kinase (MAPK) molecules and deactivate them. Therefore, MKPs play an important role in determining the magnitude and duration of MAPK activities. MKPs constitute a structurally distinct family of dual-specificity phosphatases. The MKP family members share the sequence homology and the preference for MAPK molecules, but they are different in substrate specificity among MAPK molecules, tissue distribution, subcellular localization and inducibility by extracellular stimuli. Our understanding of their protein structure, substrate recognition mechanisms, and regulatory mechanisms of the enzymatic activity has greatly increased over the past few years. Furthermore, although there are a number of MKPs, that have similar substrate specificities, non-redundant roles of MKPs have begun to be identified. Here we focus on recent findings regarding regulation and function of the MKP family members as physiological regulators of MAPK signaling.
Keywords: MAP kinase; MAP kinase phosphatase; Dual-specificity phosphatase;

In vivo, eukaryotic cells are subjected simultaneously to a broad array of signals ranging from mitogens and inflammatory inputs to environmental stresses and developmental cues. The combinatorial nature of cellular signaling necessitates that a cell integrate its signal transduction pathways so as to implement rapidly and efficiently an appropriate suite of responses. Emerging evidence indicates that, over the course of evolution, cells have developed multiprotein signaling complexes, or “signalosomes” that mediate the coordinate regulation of different signaling pathways. Such molecular signal integration contrasts with the classical notion of signaling complexes assembled by scaffold proteins—entities that function to segregate specific pathways from one another. This review will focus on two signal integrating multiprotein complexes that involve Raf family kinases: the MLK3-B-Raf–Raf-1 complex and the Raf-1–Mst-2 complex.
Keywords: Raf; MAPK; MLK3; NF2/merlin; Mst2/Hippo; Cell proliferation;

Clinical experience of MEK inhibitors in cancer therapy by Ding Wang; Scott A. Boerner; James D. Winkler; Patricia M. LoRusso (1248-1255).
Finding new therapies to assist in the treatment of cancer is a major challenge of clinical research. Small molecules that inhibit different molecular targets at the different levels of the MAPK pathway have been developed. Several MEK inhibitors have been examined in early-phase clinical trials and the current state of clinical results using these therapies is presented here.
Keywords: MEK; MAPK; Targeted therapy;

RAF kinases and mitochondria by Antoine Galmiche; Jochen Fueller (1256-1262).
Over the past decade, several investigators reported that a fraction of the RAF kinases are recruited to the mitochondria. Although we are still far from a global understanding of the molecular consequences of RAF translocation on mitochondrial physiology and metabolism, the recent description of some molecular interactions that are established by C-RAF in this organelle, principally with the proteins Bcl-2 and Bag-1, provides some clues. Here, we discuss the possible contribution of RAF targeting to mitochondria to their modulation of apoptosis signaling, as well as to this organelle's physiology. In addition, we discuss the possible modulation of the mitochondrial metabolism by RAF oncogenes in the context of cancer.
Keywords: RAF kinases; Mitochondria; Apoptosis; Bcl-2; Metabolism;

Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance by James A. McCubrey; Linda S. Steelman; William H. Chappell; Stephen L. Abrams; Ellis W.T. Wong; Fumin Chang; Brian Lehmann; David M. Terrian; Michele Milella; Agostino Tafuri; Franca Stivala; Massimo Libra; Jorg Basecke; Camilla Evangelisti; Alberto M. Martelli; Richard A. Franklin (1263-1284).
Growth factors and mitogens use the Ras/Raf/MEK/ERK signaling cascade to transmit signals from their receptors to regulate gene expression and prevent apoptosis. Some components of these pathways are mutated or aberrantly expressed in human cancer (e.g., Ras, B-Raf). Mutations also occur at genes encoding upstream receptors (e.g., EGFR and Flt-3) and chimeric chromosomal translocations (e.g., BCR-ABL) which transmit their signals through these cascades. Even in the absence of obvious genetic mutations, this pathway has been reported to be activated in over 50% of acute myelogenous leukemia and acute lymphocytic leukemia and is also frequently activated in other cancer types (e.g., breast and prostate cancers). Importantly, this increased expression is associated with a poor prognosis. The Ras/Raf/MEK/ERK and Ras/PI3K/PTEN/Akt pathways interact with each other to regulate growth and in some cases tumorigenesis. For example, in some cells, PTEN mutation may contribute to suppression of the Raf/MEK/ERK cascade due to the ability of activated Akt to phosphorylate and inactivate different Rafs. Although both of these pathways are commonly thought to have anti-apoptotic and drug resistance effects on cells, they display different cell lineage specific effects. For example, Raf/MEK/ERK is usually associated with proliferation and drug resistance of hematopoietic cells, while activation of the Raf/MEK/ERK cascade is suppressed in some prostate cancer cell lines which have mutations at PTEN and express high levels of activated Akt. Furthermore the Ras/Raf/MEK/ERK and Ras/PI3K/PTEN/Akt pathways also interact with the p53 pathway. Some of these interactions can result in controlling the activity and subcellular localization of Bim, Bak, Bax, Puma and Noxa. Raf/MEK/ERK may promote cell cycle arrest in prostate cells and this may be regulated by p53 as restoration of wild-type p53 in p53 deficient prostate cancer cells results in their enhanced sensitivity to chemotherapeutic drugs and increased expression of Raf/MEK/ERK pathway. Thus in advanced prostate cancer, it may be advantageous to induce Raf/MEK/ERK expression to promote cell cycle arrest, while in hematopoietic cancers it may be beneficial to inhibit Raf/MEK/ERK induced proliferation and drug resistance. Thus the Raf/MEK/ERK pathway has different effects on growth, prevention of apoptosis, cell cycle arrest and induction of drug resistance in cells of various lineages which may be due to the presence of functional p53 and PTEN and the expression of lineage specific factors.
Keywords: Raf/MEK/ERK; Signaling; Apoptosis; Drug resistance; PI3K/Akt; Cancer therapy;

Mitogen-activated protein kinase (MAPK) signaling pathways are key mediators of eukaryotic transcriptional responses to extracellular signals. These pathways control gene expression in a number of ways including the phosphorylation and regulation of transcription factors, co-regulatory proteins and chromatin proteins. MAPK pathways therefore target multiple components of transcriptional complexes at gene promoters and can regulate DNA binding, protein stability, cellular localization, transactivation or repression, and nucleosome structure. Recent work has uncovered further complexities in the mechanisms by which MAPKs control gene expression including their roles as integral components of transcription factor complexes and their interplay with other post-translational modification pathways. In this review I discuss these advances with particular focus on how MAPK signals are integrated by transcription factor complexes to provide specific transcriptional responses and how this relates to cellular function.
Keywords: Gene expression; Signal transduction; Transcription factor; Chromatin; MAP kinase; Phosphorylation;

ERK implication in cell cycle regulation by Jean-Claude Chambard; Renaud Lefloch; Jacques Pouysségur; Philippe Lenormand (1299-1310).
The Ras/Raf/MEK/ERK signaling cascade that integrates an extreme variety of extracellular stimuli into key biological responses controlling cell proliferation, differentiation or death is one of the most studied intracellular pathways. Here we present some evidences that have been accumulated over the last 15 years proving the requirement of ERK in the control of cell proliferation. In this review we focus (i) on the spatio-temporal control of ERK signaling, (ii) on the key cellular components linking extracellular signals to the induction and activation of cell cycle events controlling G1 to S-phase transition and (iii) on the role of ERK in the growth factor-independent G2/M phase of the cell cycle. As ERK pathway is often co-activated with the PI3 kinase signaling, we highlight some of the key points of convergence leading to a full activation of mTOR via ERK and AKT synergies. Finally, ERK and AKT targets being constitutively activated in so many human cancers, we briefly touched the cure issue of using more specific drugs in rationally selected cancer patients.
Keywords: MEK; ERK; Signaling cascade; Cell Cycle; Phosphorylation; Cancer;

Signaling pathways that activate different mitogen-activated protein kinases (MAPKs) elicit many of the responses that are evoked in cells by changes in certain environmental conditions and upon exposure to a variety of hormonal and other stimuli. These pathways were first elucidated in the unicellular eukaryote Saccharomyces cerevisiae (budding yeast). Studies of MAPK pathways in this organism continue to be especially informative in revealing the molecular mechanisms by which MAPK cascades operate, propagate signals, modulate cellular processes, and are controlled by regulatory factors both internal to and external to the pathways. Here we highlight recent advances and new insights about MAPK-based signaling that have been made through studies in yeast, which provide lessons directly applicable to, and that enhance our understanding of, MAPK-mediated signaling in mammalian cells.
Keywords: Mitogen_activated protein kinase; MAPK; Fus3; Kss1; Hog1; Mpk1/Slt2; Smk1; Mitogen_activated protein kinase kinase; MAPKK; Ste7; Pbs2; Mkk1; Mkk2; Mitogen_activated protein kinase kinase kinase; MAPKKK; Ste11; Ssk2; Ssk22; Bck1; Mitogen_activated protein kinase kinase kinase kinase; MAPKKKK; Pkc1; p21_activated protein kinase; PAK; Ste20; 5′_AMP_activated protein kinase; AMPK; Snf1; 3′,5′_cyclic AMP_dependent protein kinase; PKA; Tpk1; Tpk2; Tpk3; Pheromone response; Filamentous growth response; Hyperosmotic stress response; Cell wall integrity; Signaling; Meiosis and sporulation; Signal transduction mechanisms; Signal propagation; Signaling fidelity; Spatial and temporal regulation; Yeast; Saccharomyces cerevisiae; Baker's yeast; Budding yeast;

c-Jun N-terminal kinases (JNKs), also referred to as stress-activated kinases (SAPKs), were initially characterized by their activation in response to cell stress such as UV irradiation. JNK/SAPKs have since been characterized to be involved in proliferation, apoptosis, motility, metabolism and DNA repair. Dysregulated JNK signaling is now believed to contribute to many diseases involving neurodegeneration, chronic inflammation, birth defects, cancer and ischemia/reperfusion injury. In this review, we present our current understanding of JNK regulation and their involvement in homeostasis and dysregulation in human disease.
Keywords: c-Jun N-terminal Kinase (JNK); Stress-activated Protein Kinase (SAPK); Ischemia; Apoptosis; Metabolic regulation; Obesity; Neurodegeneration; Chronic inflammation;

Physiological roles of MKK4 and MKK7: Insights from animal models by Xin Wang; Auriane Destrument; Cathy Tournier (1349-1357).
c-Jun NH2-terminal protein kinase (JNK) is a mitogen-activated protein kinase (MAPK) involved in the regulation of numerous physiological processes during development and in response to stress. Its activity is increased upon phosphorylation by the MAPK kinases, MKK4 and MKK7. Similar to the early embryonic death of mice caused by the targeted deletion of the jnk genes, mice lacking mkk4 or mkk7 die before birth. The inability of MKK4 and MKK7 to compensate for each other's functions in vivo is consistent with their synergistic effect in mediating JNK activation. However, the phenotypic analysis of the mutant mouse embryos indicates that MKK4 and MKK7 have specific roles that may be due to their selective regulation by extracellular stimuli and their distinct tissue distribution. MKK4 and MKK7 also have different biochemical properties. For example, whereas MKK4 can activate p38 MAPK, MKK7 functions as a specific activator of JNK. Here we summarize the studies that have shed light on the mechanism of activation of MKK4 and MKK7 and on their physiological functions.
Keywords: MAPK; JNK; MKK4; SEK1; MKK7; JNKK; Stress;

Mammalian p38 mitogen-activated protein kinases (MAPKs) are activated by a wide range of cellular stresses as well as in response to inflammatory cytokines. There are four members of the p38MAPK family (p38α, p38β, p38γ and p38δ) which are about 60% identical in their amino acid sequence but differ in their expression patterns, substrate specificities and sensitivities to chemical inhibitors such as SB203580. A large body of evidences indicates that p38MAPK activity is critical for normal immune and inflammatory response. The p38MAPK pathway is a key regulator of pro-inflammatory cytokines biosynthesis at the transcriptional and translational levels, which makes different components of this pathway potential targets for the treatment of autoimmune and inflammatory diseases. However, recent studies have shed light on the broad effect of p38MAPK activation in the control of many other aspects of the physiology of the cell, such as control of cell cycle or cytoskeleton remodelling. Here we focus on these emergent roles of p38MAPKs and their implication in different pathologies.
Keywords: p38 MAP kinase; Cellular stress; Pro-inflammatory cytokines; Cellular differentiation; Inflammatory disease; Cancer;

Atypical mitogen-activated protein kinases: Structure, regulation and functions by Phillipe Coulombe; Sylvain Meloche (1376-1387).
Mitogen-activated protein (MAP) kinases are a family of serine/threonine kinases that play a central role in transducing extracellular cues into a variety of intracellular responses ranging from lineage specification to cell division and adaptation. Fourteen MAP kinase genes have been identified in the human genome, which define 7 distinct MAP kinase signaling pathways. MAP kinases can be classified into conventional or atypical enzymes, based on their ability to get phosphorylated and activated by members of the MAP kinase kinase (MAPKK)/MEK family. Conventional MAP kinases comprise ERK1/ERK2, p38s, JNKs, and ERK5, which are all substrates of MAPKKs. Atypical MAP kinases include ERK3/ERK4, NLK and ERK7. Much less is known about the regulation, substrate specificity and physiological functions of atypical MAP kinases.
Keywords: Protein phosphorylation; MAP kinase; Extracellular signal regulated kinase; Nemo-like kinase; Structure; Substrate specificity;