Elsevier

Pharmacological Research

Volume 66, Issue 2, August 2012, Pages 105-143
Pharmacological Research

Invited review
ERK1/2 MAP kinases: Structure, function, and regulation

https://doi.org/10.1016/j.phrs.2012.04.005Get rights and content

Abstract

ERK1 and ERK2 are related protein-serine/threonine kinases that participate in the Ras-Raf-MEK-ERK signal transduction cascade. This cascade participates in the regulation of a large variety of processes including cell adhesion, cell cycle progression, cell migration, cell survival, differentiation, metabolism, proliferation, and transcription. MEK1/2 catalyze the phosphorylation of human ERK1/2 at Tyr204/187 and then Thr202/185. The phosphorylation of both tyrosine and threonine is required for enzyme activation. Whereas the Raf kinase and MEK families have narrow substrate specificity, ERK1/2 catalyze the phosphorylation of hundreds of cytoplasmic and nuclear substrates including regulatory molecules and transcription factors. ERK1/2 are proline-directed kinases that preferentially catalyze the phosphorylation of substrates containing a Pro-Xxx-Ser/Thr-Pro sequence. Besides this primary structure requirement, many ERK1/2 substrates possess a D-docking site, an F-docking site, or both. A variety of scaffold proteins including KSR1/2, IQGAP1, MP1, β-Arrestin1/2 participate in the regulation of the ERK1/2 MAP kinase cascade. The regulatory dephosphorylation of ERK1/2 is mediated by protein-tyrosine specific phosphatases, protein-serine/threonine phosphatases, and dual specificity phosphatases. The combination of kinases and phosphatases make the overall process reversible. The ERK1/2 catalyzed phosphorylation of nuclear transcription factors including those of Ets, Elk, and c-Fos represents an important function and requires the translocation of ERK1/2 into the nucleus by active and passive processes involving the nuclear pore. These transcription factors participate in the immediate early gene response. The activity of the Ras-Raf-MEK-ERK cascade is increased in about one-third of all human cancers, and inhibition of components of this cascade by targeted inhibitors represents an important anti-tumor strategy. Thus far, however, only inhibition of mutant B-Raf (Val600Glu) has been found to be therapeutically efficacious.

Introduction

Protein kinases play a predominant regulatory role in nearly every aspect of cell biology [1]. The human protein kinase family consists of 518 genes, which correspond to about 1.7% of the genome, thereby making it one of the largest gene families [2]. Protein kinases catalyze the reaction illustrated in Fig. 1. Note that the phosphoryl group (PO32−) and not the phosphate group (PO42−) is transferred to the protein substrate. Based upon the nature of the phosphorylated single bondOH group, these proteins are classified as protein-serine/threonine kinases (385 members), protein-tyrosine kinases (90 members), and tyrosine-kinase like proteins (43 members) [2]. Moreover, there are 106 protein kinase pseudogenes. A small group of dual-specificity kinases including MEK1/2 catalyze the phosphorylation of both tyrosine and threonine in target proteins such as ERK1/2. Dual-specificity kinases belong to the protein-serine/threonine kinase family. Protein phosphorylation is the most widespread class of post-translational modification used in signal transduction. Families of protein phosphatases catalyze the dephosphorylation of proteins [3], [4] thus making phosphorylation–dephosphorylation an overall reversible process.

The mammalian MAP kinases consist of cytoplasmic protein-serine/threonine kinases that participate in the transduction of signals from the surface to the interior of the cell. This group includes the extracellular signal-regulated kinase (ERK) family, the p38 kinase family, and the c-Jun N-terminal kinase family (JNK, also known as stress-activated protein kinase or SAPK). The following enzyme forms have been described: ERK1–ERK8, p38α/β/γ/δ, and JNK1–3 [5], [6], [7]. Each MAPK signaling cascade consists of at least three components, or tiers: a MAPK kinase kinase (MAP3K), a MAPK kinase (MAP2K), and a MAPK (Fig. 2). The activated MAP kinases catalyze the phosphorylation of numerous substrate proteins including transcription factors, protein kinases and phosphatases, and other functional proteins.

Scaffold proteins, which interact with more than one component in a given cascade, mediate the activation of the MAP kinase signaling pathways. For example, the kinase suppressor of Ras (KSR) and MEK partner 1 (MP1) function as scaffolds for the ERK1/2 signaling pathway, and the JNK-interacting protein group (JIP) serves as scaffolds for the JNK pathway [9], [10]. KSR1/2 interact with B-Raf, C-Raf, MEK1/2 and ERK1/2, and MP1 interacts with MEK1/2 and ERK1/2. JIP interacts with MLK3, MKK7, and JNK. β-arrestin2 is a scaffold protein for both the ERK1/2 and JNK1–3 signaling pathways. β-Arrestin2 interacts with the Raf and ERK families and with apoptosis signal-regulating kinase (ASK1, or MAP3K5) and JNK3.

The p38 and JNK signaling pathways are activated by proinflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β or in response to cellular stresses such as genotoxic, osmotic, hypoxic, or oxidative stress [8]. The p38 signaling pathway consists of p38α/β/γ/δ, a MAP2K such as MKK3 or MKK6, and a MAP3K such as ASK1 or TAK1 (transforming growth factor-β-activated kinase 1) [11]. The p38 family plays a role in angiogenesis, cell proliferation, inflammation, and the production of cytokines, which are immunomodulating agents. The JNK pathway consists of JNK1–3, a MAP2K such as MAP2K4 (also known as SEK1) or MAP2K7, and a MAP3K such as ASK1 or TAK1 (both of which also function in the p38 pathway), MEKK1, or mixed-lineage kinase (MLK) [12]. The JNK family participates in apoptosis and the development of multiple cell types of the immune system.

Human ERK1 and ERK2 are 84% identical in sequence and share many if not all functions [13]. For this reason they will be referred to as ERK1/2. ERK1/2, like nearly all protein kinases, contain unique N- and C-terminal extensions that provide signaling specificity. ERK1 contains a 17-amino-acid-residue insertion in its N-terminal extension (Fig. 3). The ERK1/2 family contains a 31-amino-acid-residue insertion within the kinase domain (kinase insert domain) that provides additional functional specificity. The cyclin-dependent kinase family also contains a comparable kinase insert domain [14]. In this review we will focus on the biochemistry and molecular biology of ERK1/2 MAP kinases.

The ERK2 enzyme has been more widely studied than the ERK1 enzyme. Human ERK2 consists of 360 amino acid residues while the rat and mouse enzyme consist of 358 residues. Although care has been taken in this review to document the enzyme species under investigation, the difference of two residues is most likely inconsequential. Human ERK1 consists of 379 amino acid residues while rat and mouse ERK1 consist of 380 residues. ERK1 and ERK2 differ more from one another in a given species more than either ERK1 or ERK2 differs among the three species.

All known cellular stimulants of the ERK1/2 pathway lead to the parallel activation of ERK1 and ERK2 [15]. Furthermore, Robbins et al. demonstrated that bacterially expressed ERK1 and ERK2 possess identical substrate specific activity in vitro [16]. Of course not all ERK1/2 substrates were known then, or now. Lefloch et al. observed that the activation ratio of ERK1/ERK2 in cells corresponds with their expression ratio indicating that the isoforms are activated in parallel [17]. Despite numerous efforts to establish differences, the functions of the two isoforms are similar. Gene ablation studies have provided provisional evidence for differential functions of ERK1 and ERK2, as described next.

Yao et al. reported that ERK1 and ERK2 are not entirely functionally redundant [18]. The erk1 gene is dispensable for the development of mice, but ablation of the erk2 gene is embryonic lethal. Pagès et al. [19] and Nekrasova et al. [20] found that erk1-deficient mice were viable, fertile, and of normal size. However, thymocyte maturation beyond the CD4+CD8+ stage was reduced by half in erk1−/− mice, with a similar diminution in the thymocyte subpopulation expressing high levels of T cell receptor (CDhigh) [19]. Thus, ERK1 appears to play an important role in thymocyte development.

Yao et al. found that ablation of erk2 in mice is embryonic lethal [18]. They reported that these mice fail to form mesoderm. Although erk2-null embryonic stem (ES) cells exhibit augmented ERK1 phosphorylation following cellular stimulation, they exhibit reduced total ERK activity and decreased downstream RSK phosphorylation; yet embryonic stem cell proliferation is unaffected. Under these conditions in vitro, ERK1 is apparently able to compensate for ERK2 loss. Hatano et al. found that the development of placental vasculature is severely impaired in erk2-deficient mice, which leads to embryonic lethality [21]. Moreover, Saba-El-Leil et al. observed that mouse embryonic trophoblast development is impaired in erk2-deficient mice [22]. They found that ERK1 is widely expressed in wild-type and erk2-null mouse embryos. These studies taken together suggested that ERK1 is unable to compensate for ERK2 deficiency in vivo. However, does the embryonic lethality of erk2−/− mice, but not erk1−/− mice, represent a difference in function or a difference in isoform expression?

Lefloch et al. examined the role of ERK1 and ERK2 expression on their effects in cells and in whole animals [17]. Although erk1−/−, but not erk2−/−, mice survive, they observed that an unfavorable embryonic outcome results when an erk1 allele is not expressed in mice expressing a single erk2 allele. Based upon a series of gene ablation experiments, they conclude that erk gene dosage is critical for mouse survival. They observed that no animal can survive with only one erk allele. However, mice with two erk2 alleles or with one erk1 allele and one erk2 allele are able to survive. Since ERK2 expression exceeds that of ERK1 in most cells, they ascribe the findings of the severe effect of knocking out ERK2 expression more to the role of diminishing total ERK content as opposed to decreasing the expression of a protein with unique biological functions [17]. Thus, whether functions exist that are unique or preferred to one or the other ERK1/2 isoform is still an open question. At one time or another during the lifetime of an animal, ERK1 or ERK2 may perform functions unique to that isoform. However, the detection of such distinctive functions will be difficult to pinpoint.

ERK1/2 are ubiquitously expressed hydrophilic non-receptor proteins that participate in the Ras-Raf-MEK-ERK signal transduction cascade, which is sometimes denoted as the mitogen-activated protein kinase (MAPK) cascade [23]. This cascade participates in the regulation of a large variety of processes including cell adhesion, cell cycle progression, cell migration, cell survival, differentiation, metabolism, proliferation, and transcription. Moreover, oncogenic mutations in human KRAS occur in about 58% of pancreatic, 33% of colorectal, and 31% of biliary cancers, and NRAS mutations occur in about 18% of melanomas [24]. Overall, the RAS genes are activated in about 30% of all human cancers [25]. Activating mutations in RAF occur in perhaps 7% of all human cancers [26], [27]. For example, BRAF mutations occur in about 40–60% of melanomas, 40% of thyroid cancers, 30% of ovarian cancers, and 20% of colorectal cancers [26], [27]. The Ras-Raf-MEK-ERK pathway is upregulated in a variety of cancers even in the absence of oncogenic mutations.

H-Ras, K-Ras, and N-Ras, three gene products, have a molecular weight of about 21 kDa. These molecules function as molecular switches as an inactive Ras-GDP is converted into an active Ras-GTP in a process that is mediated by a guanine nucleotide exchange factor (GEF), which is also known as Sos1/2 (from Drosophila son of sevenless) [28]. This conversion of Ras-GDP to Ras-GTP is promoted by the action of several receptor protein-tyrosine kinases including those of the EGFR family, the insulin-like growth factor receptor, the VEGFR family, and many others [29]. Ligand-induced receptor dimerization promotes receptor autophosphorylation in trans thus resulting in receptor activation [30]. Such phosphorylated residues serve as binding sites for proteins that contain a Src homology 2 (SH2) domain, a phosphotyrosine binding domain (PTB), or both domains, which are expressed in Shc [31]. Shc in turn recruits Grb2 (growth factor receptor-bound protein 2) and Sos1/2 leading to Ras activation. The best characterized route of Ras activation occurs at the plasma membrane and is mediated by Sos1/2, as noted above. Activated G-protein coupled receptors and integrins, which are integral membrane proteins, can also lead to the formation of active Ras-GTP. Ras-GTP has about a dozen downstream effector pathways including the Raf-MEK-ERK signaling cascade [28]. Active Ras-GTP is converted to the inactive Ras-GDP as the intrinsic Ras-GTPase activity is stimulated by GTPase activating protein (GAP) [32].

Ras-GTP leads to the activation of the Raf kinase family (A-, B-, and C-Raf) by an intricate multistage process that involves homodimer and heterodimer formation [33]. The Raf kinases have restricted substrate specificity and catalyze the phosphorylation and activation of MEK1 and MEK2. MEK1/2 are dual-specificity protein kinases that mediate the phosphorylation of tyrosine and threonine in ERK1 and ERK2, their only known physiological substrates [34], [35]. This phosphorylation activates ERK1/2, which are protein-serine/threonine kinases. Unlike the Raf kinases and MEK1/2, which have narrow substrate specificity, ERK1 and ERK2 have more than 175 documented cytoplasmic and nuclear substrates [36] and surely more will be found. While the Raf isoforms are the primary MAP3Ks in the ERK1/2 module, MEKK1, Mos, and COT (MAP3K8, or TPL2) are additional ERK1/2 MAP3Ks utilized in more restricted cell type- and stimulation-specific situations (reviewed in Refs. [11], [37]).

One potential of a signaling cascade is that of amplification. One protein kinase can catalyze the phosphorylation of many substrate molecules. If the substrate is a protein kinase, it too can catalyze the phosphorylation of many substrate molecules, etc. Fujioka et al. measured the concentrations of Ras, Raf, MEK, and ERK in human HeLa and African green monkey COS-7 cells and obtained the results shown in Table 1 [38]. The concentration of Ras in HeLa cells is about 30 times that of Raf. The concentration of MEK is about 100 times that of Raf, but the concentration of ERK is only 2/3rds that of MEK. Thus, in the ERK signaling module, the possibility of a 100-fold amplification from Raf to MEK exists. In contrast, such amplification from MEK to ERK is unlikely. The likelihood that one kinase can activate 1000 kinase substrates and the second kinase can activate 1000 substrates for a total amplification of 1 × 106 is remote for the Raf-MEK-ERK module. Thus, amplification of a signaling cascade is not obligatory. Moreover, the original definition of a cascade is a series of waterfalls. The amount of water that goes over the last waterfall is the same as that going over the first, and amplification in a waterfall cascade is impossible. Under conditions whereby EGF stimulation leads to the phosphorylation (activation) of 5% of endogenous MEK in HeLa cells, Fujioka et al. observed that about 60% of endogenous ERK is phosphorylated [38]. This observation is consistent with the notion that an approximate 10-fold amplification occurs in response to stimulation. This finding indicates that significant amplification took place, but not a hypothetical increase amounting to several orders of magnitude.

ERK1/2 MAP kinases are activated in a wide variety of cell types by mitogenic and other stimuli [39], [40]. 1n 1987, Ray and Sturgill investigated the insulin-stimulated activation of a microtubule-associated protein 2 kinase (MAP2 kinase) from mouse 3T3-L1 adipocytes [41]. In 1989, Silliman and Sturgill renamed this enzyme “mitogen-activated protein” kinase maintaining the MAP kinase acronym [42]. Boulton et al. cloned the cDNA of rat ERK1 [43], purified the enzyme from a rat fibroblast cell line that over expresses human insulin receptors (Rat 1 HIRc B cells) [44], and cloned the cDNA of two additional family members (ERK2 and ERK3) [45]. Boulton et al. coined the acronym ERK for extracellular signal-regulated protein kinase and applied it to MAP2 kinase because of the wide variety of extracellular signals that lead to its activation [45]. Early studies indicated that these enzymes are activated following cellular stimulation by bradykinin, epidermal growth factor, fibroblast growth factor, insulin, insulin-like growth factor-1, nerve growth factor, and platelet-derived growth factor [39]. ERK1/2 are also activated by cytokines, osmotic stress, and activated seven transmembrane G-protein coupled receptors [11].

In addition to the classical MEK1/2-ERK1/2 signaling component, MEK1b and ERK1c constitute a distinct signaling pathway [46]. MEK1b and ERK1c are alternatively spliced forms of MEK1 and ERK1, respectively. Zheng and Guan reported that human MEK1b, which possesses a 23-amino-acid deletion in its kinase domain, is unable to activate recombinant human ERK1 or ERK2 [47]. Aebersold et al. showed that human ERK1c results from the insertion of intron 7 into the coding region of ERK1 [48]. The insertion contains a stop codon leading to the expression of a 41-kDa protein that contains 18 different amino acids that replace the C-terminus of ERK1. ERK1c influences mitotic Golgi fragmentation and mitosis progression. Shaul et al. demonstrated that MEK1b, which is unable to activate ERK1 or ERK2, activates ERK1c [46]. This provides a signaling component consisting of MEK1b-ERK1c (Fig. 2). However, the mechanism of activation of MEK1b is unclear [46]. Yung et al. reported that a different alternatively spliced form of ERK1 (ERK1b) occurs in rat [49].

The Ras-Raf-MEK-ERK signaling cascade is dysregulated in a variety of diseases including brain injury, cancer, cardiac hypertrophy, diabetes, and inflammation [50], [51], [52], [53], [54], [55]. Moreover, oncogenic mutations of RAS or BRAF are responsible for a large proportion of human cancers as noted earlier in this section [25], [26]. Owing to the importance of protein kinases in general and in the ERK1/2 signaling cascade in particular, protein kinases represent bona fide drug targets that are receiving considerable attention from a large cadre of biomedical scientists [56]. Anecdotal evidence indicates that perhaps one-quarter to one-third of drug discovery research performed by commercial pharmaceutical firms is directed toward protein kinases. Moreover, a significant fraction of academic research is directed toward understanding the molecular biology and physiology of protein kinase signaling pathways.

Section snippets

Catalytic residues in the N- and C-lobes

ERK1/2, like all protein kinases, have a small amino-terminal lobe and large carboxyterminal lobe that contain several conserved α-helices and β-strands, first described by Knighton et al. for PKA [57]. The small lobe is dominated by a five-stranded antiparallel β-sheet (β1–β5) [58]. It also contains an important and conserved αC-helix that occurs in active or inactive orientations. The small lobe contains a conserved glycine-rich (GxGxxG) ATP-phosphate-binding loop, sometimes called the

Nuclear substrates

Activated ERK1/2 catalyzes the phosphorylation of transcription factors and some of their regulators [36], [82]. ERK1/2 nuclear targets include the ternary complex factor (TCF) family of transcription factors. These proteins play a major role in inducing the expression of the immediate early genes (IEGs). The immediate early gene products such as c-Fos and c-Myc induce late-response genes that promote cell survival, cell division, and cell motility [6], [83], [84]. The ERK1/2 cascade also

ERK1/2 enzyme–substrate and enzyme–protein interactions

ERK1/2 catalyze the phosphorylation of serine/threonine residues that occur in the sequence Ser/Thr-Pro [101]. Proline at the P + 1 position is the most reliable primary sequence determinant of ERK1/2 and other MAP kinase substrates. The phosphorylation site is numbered 0 (zero), the residue immediately after the phosphorylation site is +1, and the residue immediately before the phosphorylation site is −1. The requirement for proline arises from the nature of the ERK1/2 binding site. Many protein

Scaffolds and anchors

Scaffolds play a pivotal role in the spatial and temporal regulation of the ERK1/2 signaling cascade. Scaffolds are proteins that bind to more than one component of a signaling module, and they regulate and integrate overall signal transduction [118], [119]. Binding multiple components of a signaling cascade brings them into close proximity and facilitates the efficient propagation of the signal while also segregating the module from related pathways. However, scaffolds have the potential to

Nuclear and cytoplasmic localization of proteins

The nucleus is the defining feature of eukaryotic cells. It segregates the chromosomes and transcriptional machinery from the translational and metabolic machinery in the cytoplasm. The nucleus is separated from the cytoplasm by a double membrane envelope that allows for the selective entrance of proteins of molecular weight greater than 40 kDa through specialized nuclear pore complexes (NPC) [96], [98]. Smaller proteins, ions, and metabolites pass through the nuclear pore by diffusion. The

MAP kinase phosphatases

The dephosphorylation of bisphosphorylated and activated MAP kinases plays a key role in regulating the magnitude and duration of kinase activation and also the nature of the physiological responses [196]. As noted in Section 2.3, removal of only one of the two phosphates that occur within the activation lip of ERK2 results in an inactive kinase [74]. The MAP kinase phosphatases (MKPs) are divided into three major categories depending on their preference for catalyzing the dephosphorylation of

General properties of clinical protein kinase inhibitors

There are currently 15 low molecular weight protein kinase inhibitors that have been approved for use by the FDA in the United States (Table 8). There are also four large molecule monoclonal antibodies that target protein-tyrosine kinases, which include bevacizumab (binds VEGF, a VEGFR family protein-tyrosine kinase activating ligand), cetuximab (targets EGFR, or HER1), panitumumab (targets EGFR, or HER1), and trastuzumab (targets ErbB2, or HER2). See //www.accessdata.fda.gov/scripts/cder/drugsatfda/

Phosphorylated proteins and protein kinases

Casein and phosvitin (vitellinic acid, vitellin) are two of the earliest known phosphoproteins [239]. Casein occurs in milk and contains about 3% phosphorus by weight [240]. Phosvitin occurs in egg yolk and contains about 10% phosphorus by weight, which is among the most highly phosphorylated proteins in nature (about one phosphate group for every two amino acid residues). Following acid hydrolysis, Lipmann and Levine identified serine phosphate as the phosphorylated component in phosvitin in

Conflict of interest

The author is unaware of any affiliations, memberships, or financial holdings that might be perceived as affecting the objectivity of this review.

References (270)

  • R. Roskoski

    MEK1/2 dual-specificity protein kinases: structure and regulation

    Biochemical and Biophysical Research Communications

    (2012)
  • Y.D. Shaul et al.

    The MEK/ERK cascade: from signaling specificity to diverse functions

    Biochimica et Biophysica Acta

    (2007)
  • A. Fujioka et al.

    Dynamics of the Ras/ERK MAPK cascade as monitored by fluorescent probes

    Journal of Biological Chemistry

    (2006)
  • C.C. Silliman et al.

    Phosphorylation of microtubule-associated protein 2 by MAP kinase primarily involves the projection domain

    Biochemical and Biophysical Research Communications

    (1989)
  • T.G. Boulton et al.

    ERKs: a family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF

    Cell

    (1991)
  • C.F. Zheng et al.

    Properties of MEKs, the kinases that phosphorylate and activate the extracellular signal-regulated kinases

    Journal of Biological Chemistry

    (1993)
  • Y. Yung et al.

    ERK1b, a 46-kDa ERK isoform that is differentially regulated by MEK

    Journal of Biological Chemistry

    (2000)
  • E.K. Kim et al.

    Pathological roles of MAPK signaling pathways in human diseases

    Biochimica et Biophysica Acta

    (2010)
  • W.E. Tidyman et al.

    The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation

    Current Opinion in Genetics and Development

    (2009)
  • J.F. Tanti et al.

    Cellular mechanisms of insulin resistance: role of stress-regulated serine kinases and insulin receptor substrates (IRS) serine phosphorylation

    Current Opinion in Pharmacology

    (2009)
  • C. Montagut et al.

    Targeting the RAF-MEK-ERK pathway in cancer therapy

    Cancer Letters

    (2009)
  • S.S. Taylor et al.

    Protein kinases: evolution of dynamic regulatory proteins

    Trends in Biochemical Sciences

    (2011)
  • C.S. Gibbs et al.

    Rational scanning mutagenesis of a protein kinase identifies functional regions involved in catalysis and substrate interactions

    Journal of Biological Chemistry

    (1991)
  • P.A. Schwartz et al.

    Protein kinase biochemistry and drug discovery

    Bioorganic Chemistry

    (2011)
  • A.P. Kornev et al.

    Defining the conserved internal architecture of a protein kinase

    Biochimica et Biophysica Acta

    (2010)
  • B.J. Canagarajah et al.

    Activation mechanism of the MAP kinase ERK2 by dual phosphorylation

    Cell

    (1997)
  • T.A. Haystead et al.

    Ordered phosphorylation of p42mapk by MAP kinase kinase

    FEBS Letters

    (1992)
  • J.E. Ferrell et al.

    Mechanistic studies of the dual phosphorylation of mitogen-activated protein kinase

    Journal of Biological Chemistry

    (1997)
  • P.J. Eichhorn et al.

    Protein phosphatase 2A regulatory subunits and cancer

    Biochimica et Biophysica Acta

    (2009)
  • C.N. Prowse et al.

    Mechanism of activation of ERK2 by dual phosphorylation

    Journal of Biological Chemistry

    (2001)
  • M.C. Mendoza et al.

    The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation

    Trends in Biochemical Sciences

    (2011)
  • L.O. Murphy et al.

    MAPK signal specificity: the right place at the right time

    Trends in Biochemical Sciences

    (2006)
  • G. Buchwalter et al.

    Ets ternary complex transcription factors

    Gene

    (2004)
  • T. Jamali et al.

    Nuclear pore complex: biochemistry and biophysics of nucleocytoplasmic transport in health and disease

    International Review of Cell and Molecular Biology

    (2011)
  • G. Manning et al.

    The protein kinase complement of the human genome

    Science

    (2002)
  • Bononi A, Agnoletto C, De Marchi E, Marchi S, Patergnani S, Bonora M, et al. Protein kinases and phosphatases in the...
  • H.J. Schaeffer et al.

    Mitogen-activated protein kinases: specific messages from ubiquitous messengers

    Molecular and Cellular Biology

    (1999)
  • A.S. Dhillon et al.

    MAP kinase signalling pathways in cancer

    Oncogene

    (2007)
  • M. Cargnello et al.

    Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases

    Microbiology and Molecular Biology Reviews

    (2011)
  • D.K. Morrison et al.

    Regulation of MAP kinase signaling modules by scaffold proteins in mammals

    Annual Review of Cell and Developmental Biology

    (2003)
  • A.J. Whitmarsh

    The JIP family of MAPK scaffold proteins

    Biochemical Society Transactions

    (2006)
  • M. Raman et al.

    Differential regulation and properties of MAPKs

    Oncogene

    (2007)
  • A.C. Lloyd

    Distinct functions for ERKs?

    Journal of Biology

    (2006)
  • R. Lefloch et al.

    Total ERK1/2 activity regulates cell proliferation

    Cell Cycle

    (2009)
  • R. Lefloch et al.

    Single and combined silencing of ERK1 and ERK2 reveals their positive contribution to growth signaling depending on their expression levels

    Molecular and Cellular Biology

    (2008)
  • Y. Yao et al.

    Extracellular signal-regulated kinase 2 is necessary for mesoderm differentiation

    Proceedings of the National Academy of Sciences of the United States of America

    (2003)
  • G. Pagès et al.

    Defective thymocyte maturation in p44 MAP kinase (Erk 1) knockout mice

    Science

    (1999)
  • T. Nekrasova et al.

    ERK1-deficient mice show normal T cell effector function and are highly susceptible to experimental autoimmune encephalomyelitis

    Journal of Immunology

    (2005)
  • N. Hatano et al.

    Essential role for ERK2 mitogen-activated protein kinase in placental development

    Genes to Cells

    (2003)
  • M.K. Saba-El-Leil et al.

    An essential function of the mitogen-activated protein kinase Erk2 in mouse trophoblast development

    EMBO Reports

    (2003)
  • Cited by (0)

    View full text