Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Mek

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_424

Synonyms

Historical Background

The transmission of extracellular signals to their intracellular targets is mediated by a network of interacting proteins that governs a large number of cellular processes including proliferation, differentiation, stress response, and apoptosis. One of the central components in the transmission network is the ERK cascade, which is composed of sequential phosphorylation and activation of the protein kinases Raf, MEK, ERK, and MAPKAPKs. In turn, the latter two components of the cascade phosphorylate a large number of regulatory proteins, culminating in the induction and regulation of proper downstream cellular processes. This cascade was identified in the late 1980s and early 1990s of the previous century by several research groups that studied growth factor receptor signaling. At that time it was already known that growth factor receptors operate via an integral or associated protein tyrosine kinases that, upon stimulation, rapidly phosphorylate tyrosine residues on many substrates. It was also known that the initial Tyr phosphorylation is replaced by a Ser/Thr phosphorylation, which is found on a large number of Proteins, 15–60 min after stimulation. An important approach to study the role of these phosphorylations was to establish a cellular event affected by growth factors and identify components that regulate it up to the receptor (upstream approach; [Seger and Krebs 1995]). One protein that undergoes significant Ser/Thr phosphorylation shortly after growth factor stimulation is ribosomal protein S6, which became a useful readout for this upstream approach. Due to the work of several laboratories in the 1980s it was found that the stimulated phosphorylation of S6 is mediated, in part, by RSK, which acts downstream of an enzyme that was initially termed microtubule-associated protein 2 (MAP-2) protein kinase, but later renamed mitogen-activated protein kinase ( MAP kinase; MAPK) and extracellular signal-regulated kinase (ERK; [Seger and Krebs 1995]).

As a central component in this novel pathway, ERK activation has attracted considerable attention. Soon after the cloning of ERK, it became clear that this protein kinase is activated due to phosphorylation of two residues in its activation loop (Thr183 and Tyr185 of ERK2). The phosphorylation of both these residues was found to be an essential step in ERK activation, as dephosphorylation of each of them completely abolished it. Initially, it was thought that the Tyr phosphorylation can be mediated by tyrosine kinases such as the growth factor receptors, while the Thr phosphorylation is mediated either by autophosphorylation or by another Ser/Thr kinase. However, this thought was rapidly changed due to studies by Ahn et al. (1991) who combined inactive ERK with fractions from growth factor–stimulated cells and looked for enhanced ERK activity. These studies led to the identification of two nonreceptor ERK activating factors, which were able to induce phosphorylation of both activatory residues on ERK. Similar activators were then identified in NGF-stimulated PC-12 cells (Gomez and Cohen 1991) and, later, in many other systems as well. Subsequently, the proteins were purified and cloned, giving rise to two main proteins and one alternatively spliced isoform that were eventually termed MEK1, MEK2, and MEK1b. These were shown to be protein kinases that catalyze Ser/Thr as well as Tyr phosphorylation and, therefore, belong to the small group of dual specificity protein kinases. These two kinases are also part of a group of MAPK kinases (MAPKKs) that are the specificity determinant of the MAPK signaling cascades in mammals and in other organisms. Finally, at that stage, it was important to elucidate the mechanism of MEK activation upon stimulation. Studies in that direction revealed that MEKs are activated by phosphorylation of two Ser residues in their activation loop. The main Ser/Thr kinase that executes this phosphorylation after stimulation was found to be the proto-oncogene Raf (Kyriakis et al. 1992), but other protein kinases were shown to act as activators (e.g., MOS, MEKK1) as well (see Fig. 1). In view of the above, it is clear today that MEK1/2 are the specificity-determining components of the ERK cascade and, therefore, are central components in the regulation of proliferation and many other physiological processes (Seger and Krebs 1995).
Mek, Fig. 1

Schematic representation of the ERK1/2 MAPK pathway. For more details, see text. MEK1 regulations are emphasized

The MEK1/2 Subfamily of MAPKKs

Key intracellular mediators of extracellular signals are the mitogen-activated protein kinase (MAPK) signaling cascades. They are evolutionarily conserved from yeast to mammals and are expressed in nematodes, insects, slime molds, and plants as well. Each of the cascades is composed of three core protein kinases (MAP3K, MAPKK, and MAPK), which might be complemented in some cells and conditions by upstream MAP4K and downstream MAPK-activated protein kinase (MAPKAPK), giving rise to either 3, 4, or 5 tiered cascades. The transmission of signals within the cascades is mediated by a sequential phosphorylation and activation of the components of the cascade, whereby the downstream components transmit the signal further by phosphorylating many regulatory proteins, which further governs an array of intracellular responses. Four such MAPK cascades are currently known in mammals, named according to the components of their MAPK tier: ERK1/2, JNK, p38, and ERK5 cascades. Main specificity-determining components of the MAPK cascades are the MAPKK levels proteins, which are MEK1/2 for the ERK1/2 cascade; MKK3, 4, 6, 7 for the JNK and p38 cascades; and MEK5 for the ERK5 cascades. These kinases are unique in having a very stringent specificity toward Thr and Tyr residues in the activation loop of their cognate MAPKs. For that reason, the MAPKK are considered as the main specificity-determining components of their cognate cascades and thereby are central regulatory components of essentially all stimulated cellular processes including proliferation, differentiation, adhesion, cellular morphology, stress response, and apoptosis.

The first identified and best-studied component of the MAPKK family is MEK1, which was shown to activate specifically ERK1/2 (Bendetz-Nezer and Seger 2005). This protein (45 kDa) is encoded by one gene (MAP2K1) that also encodes an alternatively spliced isoform termed MEK1b (43 kDa). The latter is very specific to the alternatively spliced isoform of ERK1 termed ERK1c (Shaul et al. 2009). Mammals contain another gene termed MAP2K2 that encodes the close homologue MEK2 (46 kDa), which phosphorylates and activates specifically ERK1/2 as well. This is an evolutionarily conserved group of protein kinases, having very close orthologues in yeasts, worms, insects, and plants. MEK1/2, like other MAPKKs, are activated by many extracellular and intracellular stimuli. These stimuli usually transmit their signals to MEK1/2 via membranal receptors that recruit adaptor proteins, together with nucleotide exchange factors, to consequently activate the small GTPase, Ras. Active Ras, in turn, recruits the protein kinases Raf1 and B-Raf (Rafs) to the plasma membrane, where they are activated via an unknown mechanism. The Rafs are the main MAP3Ks that activate MEK1/2 by phosphorylating them on two Ser residues (Ser218, 222 in human MEK1) in their activation loops. However, the ability to induce this MEK1/2 phosphorylation is not restricted to Rafs, since under different conditions other kinases can serve as MEK kinases as well. For example, MOS acts as a MEK1/2 kinase in the reproductive system, and MEKK1 acts under stress conditions. A-Raf, MLTKα/β, TPL2, and MST1 have been implicated in the activation of MEK1/2 as well, but the conditions under which they operate are not fully understood.

MEK1/2 Activity and Its Regulation

As mentioned above, the main function of MEK1/2 is to phosphorylate and activate ERK1/2. In all species, MEK1/2 isoforms exhibit unique specificity toward the native forms of these two downstream targets, phosphorylating them nonprocessively on their activatory Thr and Tyr that are separated by Glu residue (Seger and Krebs 1995). This Thr-Glu-Tyr phosphorylation induces a big conformational change in the active pocket of ERK1/2 which, consequently, results in the activation of the proteins and the rest of the cascade. Aside from this most important role of MEK1/2 in ERK1/2 activation, these MAPKKs were implicated in additional processes, including: (1) association with ERK1/2 to induce either cytoplasmic localization of the latter in resting cells or their nuclear export at later time points after stimulation (Fukuda et al. 1997; Rubinfeld et al. 1999), (2) direct binding to DNA in gene promoters that consequently results in a direct regulation of transcription (Perry et al. 2001), and (3) regulation of the subcellular localization of PPARγ (Burgermeister and Seger 2007). These additional functions, which are not directly dependent on the kinase activity of MEK1/2, indicate that these two MAPKKs may exert their activity in a kinase-independent manner. Furthermore, these additional activities demonstrate ERK-independent functions that seem to complement the main functions of ERK1/2 in the regulation of mitogenic signals.

Being important components of the central ERK cascade and other processes, MEK1/2 activation is well regulated by various mechanisms. Like many other components of signaling cascades, the activation of MEK1/2 is transient, as their activity usually peaks 2–4 min after stimulation and returns to basal levels within 10–90 min, dependent on the stimuli and conditions. The activation is mediated by the MAP3Ks described above, while the removal of the phosphates from the two activatory Ser residues, which consequently leads to inactivation of MEK1/2, is mainly mediated by the Ser/Thr phosphatase PP2A. However, aside from the dynamic phosphorylation of the activatory Ser residues, MEK1/2 are regulated by additional phosphorylations. One such phosphorylation is that of Ser298 of MEK1 by the protein kinase Pak1, which acts downstream of the morphology regulator Rho. This phosphorylation does not activate MEK1 by itself, but seems to accelerate the Ser218/222-dependent activation, thereby serving as a convergence point of distinct signals. Other phosphorylations of MEK1 are inhibitory ones, including MEK1’s Thr286 and Thr292, which seem to inhibit mainly Ser298 phosphorylation, and MEK1’s Ser212 that inhibits the activity of MEK1/2 by an unknown mechanism. These, and other phosphorylations as well as a few docking domains described below, induce better interactions of MEK1/2 with scaffold proteins such as Paxillin, MP1, and more. These interactions can bring MEK1/2 to close proximity to their upstream activators, to ERK1/2, and to their correct site of action and, therefore, may accelerate properly situated MEK activity. In addition, the activity of MEK1/2 is also regulated by their heterologous dimerization and by varying their subcellular localization. Finally, MEK1/2 are excellent targets for synthetic inhibitors, and many such small molecular weight inhibitors (e.g., PD98059, U0126, PD184352, and AZD6244) are currently being used either in the biochemical studies of the ERK cascade or in the development of anticancer drugs (see below).

Structure–Function Relationships

Most of the structure–function relationships have been conducted on MEK1, but because of their sequence (Seger and Krebs 1995) and conformation (Ohren et al. 2004) similarities, MEK1 and MEK2 probably share many of the features identified. Human MEK1 is a 393 amino acid protein kinase that contains all known kinase subdomains and residues, including ATP binding and catalytic sites. Indeed, this protein exhibits a significant phosphorylation activity that ranges from ∼10 nmole/min/mg in basal state to ∼1 mmole/min/mg in its active state. The significant change in MEK1 activity (105 fold) is mediated by two Ser phosphorylations, as described above. The phosphorylation of both residues is essential for full catalytic MEK1 activity, while phosphorylation of just one of the Ser residues is sufficient to induce only small MEK1 activation (up to ∼15% of total activity for p-Ser222). Interestingly, phosphomimetic mutations of the two Ser residues induce a constitutive but rather low MEK1 activity, which can be used to study MEK1 functions.

As central signaling components, the activity of MEK1/2 is well regulated by interacting proteins, protein kinases, and protein phosphatases. In order to allow this regulation, MEK1/2 contain several docking domains, as well as phosphorylation sites that are spread all over the molecules (Fig. 2). Thus, the very N-terminus of MEK (residues 3–11) contains a docking domain (D-domain), which interacts specifically with the CRS/CD domain of ERK1/2 and, thereby, directly determines ERK1/2 activation (Tanoue et al. 2000). This region is also important for other MEK1 activities, including its effects on PPARγ and ERK1/2 localization. Another important domain in the N-terminus of MEK1 lies within residues 31–68. Deletion of residues 31–51, or substitution of residues within this area, causes high constitutive activation of MEK1 which, together with its phosphomimetic mutations, is used for functional MEK studies. In addition, few activatory oncogenic (see below) or Cardio-Facio-Cutaneous (CFC) syndrome–causing mutations were identified C-terminal to residue 44 (Phe53Ser, Gln56Pro, Lys57Asn, ΔLys59, and Asp67Asn). Therefore, it is likely that the 31–68 region is important for maintaining the low basal MEK1 activity. Finally, another important part in this region is its nuclear export signal (NES; residues 32–44), which determines its subcellular localization, as described below.
Mek, Fig. 2

Schematic representations of MEK1 and MEK2. The docking domains (DD), nuclear export signals (NES), activation loops (AL), proline-rich domain (PRD), domain of versatile docking (DVD, MAP3K binding), and ATP-binding site are marked. MEK1’s natural oncogenic (red) and some CFC-causing (green) mutations, as well as phosphorylation sites (yellow) are stated. Putative phosphorylation site is dashed

Based on sequence alignment, the core kinase domain of MEK1 starts at residue 74 with the ATP binding site and is stretched all the way to residue 361. This catalytic region contains several regulatory parts, including the activation loop (residues 212–225) and a proline-reach domain (PRD; residues 271–307). First, CFC-causing mutations in residues 124–130 (Pro124Leu, Gly128Val, and Tyr130Asn/Cys) as well as Glu203Gln/Lys indicate that similar to residues 31–68, these regions participate in maintaining the low basal activity of MEK1. Another important functional region is the activation loop of MEK1 containing three phosphorylation sites, including the inhibitory Ser212, and activatory Ser218 and Ser222. Finally, the third functional region of the kinase domain is PRD, which unlike other domains is somewhat different between MEK1 and MEK2. This region mediates/regulates MEK1’s interactions and activity, but the full scope of its activities still requires clarification.

The C-terminal region of MEK1 is, as yet, another regulatory part of MEK1/2. It contains the domain for versatile docking (DVD; residues 362–381), which is conserved among other MAPKKs, and seems to be important for interaction with upstream kinases (Takekawa et al. 2005). Interestingly, a region close to the DVD was also implicated in the determination of MEK1’s localization in the cytoplasm (Bendetz-Nezer and Seger 2005). In addition, Thr386, very close to the C-terminal edge of MEK1, was identified as a robust phosphorylation site that regulates MEK1 interactions. This phosphorylation, together with that of the nearby Thr384, was recently implicated in mediating the short-term nuclear translocation of MEK1 (Chuderland et al. 2008). Finally, Thr23, Ser24/25, Ser218, and Ser299 in MEK1 also serve as phosphorylation/autophosphorylation sites, but their role is not fully understood yet.

Subcellular Localization

The downstream targets of the ERK cascade are localized in various cellular organelles, including the cytoplasm, nucleus, plasma membranes, cytoskeleton, mitochondria, Golgi, and ER. However, in resting cells, the inactive MEK1/2, ERK1/2, and most of their MAPKAPKs are localized primarily in the cytoplasm (Yao and Seger 2009). This cytoplasmic localization of the various components is maintained mainly by binding to cytoplasmic anchoring proteins. In the case of MEK1/2, the anchoring proteins include KSR, β-arrestin, paxillin, MP1, Grb10, IQGAP1, and others that interact with either the D- or PR-domains of MEK1/2. These interactions also seem to be important for the rapid downstream signaling by the ERK cascade upon activation. Interestingly, MEK1/2 are localized in the cytoplasm not only by docking interactions but also due to their N-terminal CRM-dependent NES, which rapidly exports any nuclear MEK1/2, making the nucleus completely devoid of MEK1/2 molecules at this stage. Since MEK1/2 are known to interact with inactive ERK1/2 via their D-domain, the cytoplasmic MEK1/2 molecules whose D-domain is not hindered by interacting proteins can by themselves anchor ERK1/2 in the cytoplasm. Thus, it was proposed that MEK1/2 serve as main cytoplasmic anchoring proteins for ERK1/2 in nonstimulated cells and, therefore, are responsible for a significant part of the cytoplasmic distribution of these protein kinases, as well as some of their interacting proteins.

The cytoplasmic distribution of MEK1/2 and the other ERK cascade components is dramatically changed upon cellular stimulations. It was shown that upon stimulation, Rafs rapidly translocate to the plasma membrane, while ERK1/2 and RSKs translocate to the nucleus and other cellular organelles. Unlike the other components, initial studies described MEK1 as a constant cytoplasm-resident protein, both in resting cells and after stimulation. It was even proposed that the nuclear translocation of MEK1/2 may be hazardous to cells, and therefore, the NES serves as a safety system to avoid this unwanted nuclear accumulation. However, it was later shown that MEK1, and presumably MEK2, could rapidly translocate into the nucleus upon cellular stimulation. Thus, initiation of signaling via the cascade causes MEK1/2 to detach from ERK1/2 and from other anchoring molecules and translocate separately from ERK1/2 into the nucleus. The mechanism that allow this translocation involves phosphorylation of the C-terminus of MEK and a consequent binding to importin7 that escort MEK1/2 to the nucleus (Chuderland et al. 2008). Unlike ERK1/2 that can be retained in the nucleus for minutes to hours, most MEK1/2 molecules are rapidly exported back to the cytoplasm shortly after translocation due to their NES, giving rise to the apparent constant cytoplasmic distribution. The role of this rapid MEK1/2 shuttle in and out of the nucleus has not been fully resolved, but might include phosphorylation of nuclear ERK isoforms such as the alternatively spliced forms ERK1b and, to some extent, ERK1c. Another possibility is that the translocated MEK1/2 are involved in the export of ERK1/2 out of the nucleus at late stages after stimulation (Yao and Seger 2009). Finally, MEK1 can also interact with other nuclear proteins (e.g., PPARγ) via its D-domain and induce their nuclear export upon stimulation. Based on all the data described above, it is clear that the subcellular localization of MEK1/2 plays an important role in the regulation of function of the ERK1/2 cascade and probably additional signaling components upon various cellular stimulations.

MEK in Cancer

As soon as the ERK cascade was elucidated, it became clear that it plays a role in the induction and development of cancer. It was initially shown that the ERK cascade transmits signals of many oncogenes such as growth factors, growth factor receptors, and other signaling components. In particular B-Raf, which is a part of the ERK cascade, is known as a potent oncogen, especially in melanoma. Today, activation of ERK1/2 was reported in more than 85% of cancer cases, even those that are transformed by oncogenes that are thought to act downstream of the cascade, indicating that downstream components may utilize a positive feedback loop to activate the ERK cascade. In all these cases, the ERK cascade is implicated mainly in mediating uncontrolled proliferation which is one of the key features that underlie oncogenic transformation. Since MEK1/2 are the sole activators of ERK1/2, it is very likely that these components are activated in cancer as well. Staining of a limited number of cancer samples indeed confirmed the phosphorylation of MEK1/2 in cancer, but a widespread screen for MEK1/2 phosphorylation in various cancer types has not been performed as yet.

Although activating mutations of MEK1/2 that can induce transformation of tissue culture cells have been identified already in the early 1990s, early studies failed to identify oncogenic forms of MEK1/2 in tumors. However, the extensive sequencing efforts of human cancers in the last few years did identify relatively rare oncogenic mutations of MEK1 in a limited number of human cancers. Thus, the activating mutation Lys57Asn was identified in lung cancer and Asp67Asn in ovarian and column cancers. Interestingly, mutations in two inhibitory regions of MEK1 (Gln56Pro and Pro124Leu) were shown to confer resistance to MEK1/2 and B-RAF inhibition, indicating the possible activating properties of these regions in human cancers. Although activating mutations have been identified in CFC, and despite large sequencing efforts, no activating MEK2 mutations were identified in human cancer so far. The reason for this is not fully understood, but may be derived from the fact that MEK1 seems to regulate MEK2 activity by its heterodimerization (Catalanotti et al. 2009).

The involvement of the ERK cascade in cancer, and the ability of dominant negative mutants of Rafs and MEK1/2 to reverse oncogenic transformation, prompted many studies aimed to develop efficient inhibitors for components of this cascade. Indeed, several Raf inhibitors have been developed over the years, and one of them, Sorafinib, is already in clinical use for several cancer types. Efficient small molecular weight inhibitors of MEK1/2 have been developed as well. When applied to animal models, these inhibitors significantly reduced the phosphorylation of ERK1/2 and, as a consequence, inhibited the growth of tumors in these models (Sebolt-Leopold et al. 1999). Therefore, several such noncompetitive inhibitors have been used in clinical trials and indeed demonstrated impressive inhibition of ERK1/2 activity, as well as a very low toxicity. Unfortunately, at present, the efficacy of the inhibitors examined is not sufficient, even in melanomas that are driven by the oncogenic form of the MEK1/2 upstream activator B-Raf. Although it seems that recent MEK inhibitors are somewhat more successful, and likely to be approved for clinical use, new generation of MEK inhibitors should still be developed to fully exploit the centrality of MEK1/2 activity in various types of cancer.

Summary

MEK1/2 are members of the MAPKK family of signaling protein kinases. They function within the ERK signaling cascade, constituting an evolutionarily conserved group with three mammalian isoforms: MEK1, MEK1b, and MEK2. MEK1/2 are activated via phosphorylation on two Ser residues in their activation loops, and when activated, they phosphorylate ERK1/2 on their regulatory Tyr and Thr residues, thereby causing their activation. Importantly, ERK1/2 are the only known phosphorylation substrates of MEK1/2, and therefore, the latter serve as specificity determinants of the ERK cascade. However, protein and DNA interactions of MEK1 also implicate it in the regulation of the subcellular localization of ERK1/2 and PPARγ and in regulating MyoD transcription. Upon activation, MEK1/2 rapidly translocate into the nucleus and then are rapidly exported back to the cytoplasm in a mechanism involving CRM1. Significantly, the centrality of MEK1/2 and the whole ERK cascade indicate that their dysregulation may result in various diseases. Indeed, activating mutations of MEK1/2 were shown to induce developmental disorders, and additional activating mutations of MEK1 were shown to act as oncogenes in a limited number of cancer. Furthermore, MEK1/2 are sensitive to synthetic inhibitors, and several of them are currently being developed as anticancer drugs mainly for melanoma.

Notes

Acknowledgments

This work was supported by a grant from the Israel Science Foundation. RS is an incumbent of the Yale S. Lewine and Ella Miller Lewine professorial chair for cancer research.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Biological RegulationThe Weizmann Institute of ScienceRehovotIsrael