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MAP Kinases: From Intracellular Signals to Physiology and Disease

Herbert Schramek

Department of Physiology, University of Innsbruck, A-6010 Innsbruck, Austria

	Abstract

 
Although differentiated cells will usually maintain their specialized character, conversion of cellular specificities can be observed during adaptation or reparative regeneration. In pathological conditions, such as inflammation and carcinogenesis, even highly specialized cells can alter their properties, leading to a deranged control of cell differentiation and/or proliferation. Mitogen-activated protein kinases are central regulators of these processes.

	Introduction

Top Introduction MEK1/2 and their substrates Tissue-specific effects on cell... Signaling node between... Linking ERK1/2 signals to... Conclusions References

 
Mitogen-activated protein kinase (MAPK) signaling cascades are among the most widespread signaling mechanisms involved in eukaryotic cell regulation. They are activated by many different stimuli (e.g., mitogens, differentiation factors, stress signals) and participate in a diverse array of cellular programs, including cell proliferation and growth, cell differentiation, cell movement, cellular senescence, and cell death. MAPKs are activated by MAPK kinases (MAPKKs or MKKs), also referred to as MAPK/extracellular signal-regulated kinase (ERK) kinases (MEKs), which represent the central components of these three kinase regulatory signaling cascades. They are dual-specificity kinases that recognize and phosphorylate a Thr-X-Tyr motif in the activation loop of their downstream targets, the MAPKs. MEK kinases (MAPKKKs or MEKKs), on the other hand, are located directly upstream of MEKs and serve as their activators. Thus a MAPK cascade consists of three sequential protein kinase reactions (Fig. 1), which finally lead to the phosphorylation of defined MAPK substrates (e.g., transcription factors, other protein kinases, phospholipases, cytoskeleton-associated proteins) on serine/threonine residues.

View larger version (20K): [in this window] [in a new window]   FIGURE 1. The Thr-Glu-Tyr (T-E-Y) family of mitogen-activated protein kinases (MAPKs). Extracellular signal-regulated kinases (ERKs) are activated by dual phosphorylation of a Thr-Glu-Tyr motif and consist of p44ERK1, p42ERK2, p110ERK5, and p60ERK7 MAPKs. MAPK kinases (MAPKKs or MKKs), also called MAPK/ERK kinases (MEKs), represent the activators of ERKs. The magnitude and duration of ERK activation is regulated by the balance of activating kinases and inactivating phosphatases, e.g., MAPK phosphatases (MKPs). The serine/threonine kinase Raf represents a MAPKK kinase (MAPKKK) and serves as an activator of MEK1 and MEK2.

In contrast to ERK1/2, activation of ERK5, which is also known as big MAPK1 (BMK1), requires MEK5 (Fig. 1). Although ERK5 has a Thr-Glu-Tyr sequence in the activation phosphorylation site, it is strongly activated by both receptor tyrosine kinases and stresses such as oxidant and hyperosmolarity. ERK7, on the other hand, does not appear to be activated either by extracellular stimuli that typically activate ERK1 or ERK2 or by common activators of JNK and p38 pathways. Instead, this novel Thr-Glu-Tyr MAPK family member is expressed as a constitutively active kinase in serum-starved cells and can function as a negative regulator of cell growth (Fig. 1). This short review is focused on MEK1/2-induced signaling events as well as on their relevance to the physiology and pathophysiology of cell proliferation, growth, and differentiation.

	MEK1/2 and their substrates

Top Introduction MEK1/2 and their substrates Tissue-specific effects on cell... Signaling node between... Linking ERK1/2 signals to... Conclusions References

 
MEK1 and MEK2 are able to phosphorylate and activate both ERK1 as and ERK2, which represent the only known substrates of these two MAPK activators (Fig. 1). Although the two MEK isoforms are highly homologous in their primary amino acid sequence, and although they elicit similar transcriptional and morphological responses in NIH/3T3 fibroblasts, they appear to be differentially regulated by their upstream activators C-raf-1, A-raf, and B-raf in different cell types and in response to different extracellular stimuli. Furthermore, MEK1 contains a nuclear export signal that, in unstimulated cells, excludes it from the nucleus. Thus, in its inactive state, MEK1 is likely to act as a cytoplasmic anchor for ERK1 and ERK2.

MEK1-induced phosphorylation of threonine and tyrosine residues in the Thr-Glu-Tyr motif of ERK2 is both necessary and sufficient for the nuclear accumulation of this MAPK, whereas ERK2 enzymatic activity is dispensable for the translocation. Phosphorylated ERK2 has been reported to form dimers with phosphorylated and unphosphorylated ERK2, and, although disruption of dimerization by mutagenesis of ERK2 reduces its ability to accumulate in the nucleus (7), recent evidence suggests that monomeric and dimeric ERK forms can enter the nucleus by both passive diffusion and active transport mechanisms (1). Thus activation of the MEK1-ERK1/2 signaling module results in its dissociation and the formation of ERK monomers and dimers, which are (at least partially) translocated to the nucleus. Binding of activated ERK1/2 to nuclear substrates might transiently anchor ERKs in the nucleus and regulate the activity of nuclear proteins such as transcription factors. Thus ERK translocation, together with its ability to phosphorylate transcription factors, might constitute a relay between cytoplasmic and nuclear events. However, half of the ERKs in activated cells are bound to the cytoskeleton, supporting the idea that ERKs also have a function within the cytoplasm and are probably involved in cytoskeletal reorganization.

The magnitude and duration of ERK activation may be affected at many points within this signaling cascade and are regulated by the balance of both activating kinases and inactivating phosphatases. A major point of regulation, however, occurs at the ERK1/2 level and can be achieved by tyrosine-specific phosphatases, serine/threonine-specific phosphatases, or dual-specificity (threonine/tyrosine) protein phosphatases, which are also called MAPK phosphatases (MKPs) (Fig. 1). The magnitude and duration of MEK1-ERK1/2-driven signals are likely to be critical determinants of the final cell type-specific physiological outcome.

The experimental system that best illustrates this is the differentiation/proliferation model of cultured rat pheochromocytoma 12 (PC-12) cells (Table 1). These cells proliferate in response to epidermal growth factor, whereas exposure to nerve growth factor or basic fibroblast growth factor causes cell differentiation marked by neurite outgrowth and cell cycle arrest in G₁. The differential response is largely governed by the ability of nerve growth factor, but not epidermal growth factor, to cause sustained activation and nuclear translocation of ERK1/2. This prolonged activation can last for several hours and appears to be necessary to maintain the differentiated state and cell survival. Interestingly, and in contrast to PC-12 cells, sustained activation of ERKs in fibroblasts leads to cell growth and transformation. In both cases, however, nuclear translocation of ERK occurs only in response to prolonged activation, suggesting that the final events responsible for the differentiation of PC-12 cells or mitogenesis of fibroblasts involve phosphorylation of nuclear targets.

	Tissue-specific effects on cell differentiation

Top Introduction MEK1/2 and their substrates Tissue-specific effects on cell... Signaling node between... Linking ERK1/2 signals to... Conclusions References

 
Similar to the results obtained in PC-12 cells, a role for MEK1-ERK1/2 in the differentiation of blood cells has been reported by several laboratories (Table 1). Expression of constitutively active MEK1 (caMEK1) in two human erythroleukemia cell lines, K526 and CMK, leads to inhibition of cell growth, induction of a characteristic megakaryocytic morphology, and cell surface expression of integrin-_IIbß₃, an adhesion receptor specifically expressed in platelets. In addition, the expression of globin genes in K562 cells is blocked by elevated MEK1-ERK1/2 activity and is upregulated by MEK inhibition, suggesting that this signaling module promotes megakaryocyte differentiation at the same time that it suppresses erythroid differentiation. Moreover, results obtained in ERK1 knockout mice demonstrate that ERK1 is critically required for the differentiation of double- to single-positive thymocytes and for thymocyte proliferation (Table 1). The inhibition of thymocyte-positive selection and of in vitro proliferation observed in ERK1 knockout mice is in agreement with the results obtained in mice expressing dominant-negative Ras, Raf, or MEK1 but is inconsistent with the observation that thymocyte proliferation is not affected in mice expressing dominant-negative MEK1.

MAPKs also seem to be involved in the regulation of distinct stages of skeletal muscle differentiation. On mitogen withdrawal from C₂C₁₂ myoblasts, ERK2 is inactivated concomitant with upregulation of muscle-specific genes such as MyoD and myogenin, suggesting that inactivation of ERK2 might be required for C₂C₁₂ myoblasts to initiate myogenesis (Table 1). Overexpression of MKP1 is sufficient to interfere with both endogenous ERK2 activity and myoblast growth and, in addition, is able to initiate the process of muscle-specific gene expression, analogous to that of mitogen withdrawal. However, expression of endogenous MKP1 declines in differentiated multinucleated myotubes, which might be required for the process of myotube formation later during myogenesis. Besides its role in skeletal muscle differentiation, transfection studies utilizing caMEK1 and dominant-negative MEK1 constructs in rat ventricular cardiomyocytes revealed that MEK1 can induce a pattern of gene expression typical of the hypertrophic cell phenotype (Table 1).

Evidence implicating ERKs in insulin-induced adipocyte differentiation from NIH/3T3-L1 fibroblasts is conflicting: although ERK antisense oligonucleotides, used to inhibit ERK activation in response to insulin, successfully blocked insulin-induced adipocyte differentiation of NIH/3T3-L1 fibroblasts, expression of caMEK1 has recently been shown to negatively regulate insulin-induced adipocyte differentiation (Table 1). Because differentiation could be activated by v-raf in the absence of ERK activity, it appears that in NIH/3T3-L1 fibroblasts the primary effect of MEK1-ERK is to negatively regulate adipogenesis, whereas v-raf may positively regulate differentiation through alternative pathways.

Our lab recently used Madin-Darby canine kidney (MDCK) cell lines, which retain differentiated properties of renal tubular epithelium, to study the role of MAPKs in the regulation of renal epithelial cell differentiation, proliferation, and invasion. Evidence from three independent experimental approaches in these cells suggests that sustained activation of the MEK1-ERK2 signaling module leads to epithelial dedifferentiation, failure of morphogenesis, and expression of a highly invasive cell phenotype: 1) In alkali-dedifferentiated MDCK-C7Focus (C7F) cells, reduction of ERK1 protein expression and an increase in basal and serum-stimulated ERK2 activity is associated with a stable switch toward a mesenchymal-like cell phenotype. 2) Long-term incubation in the presence of ochratoxin A, a nephrotoxin and secondary fungal metabolite, which has been reported to increase the incidence of Balkan endemic nephropathy and of renal carcinomas as well as adenomas in rats, induces a dedifferentiation of epithelial MDCK-C7 cells associated with sustained ERK1/2 activation. 3) Stable expression of a caMEK1 mutant in MDCK-C7 cells (C7caMEK1 cells) results in pronounced phenotypic changes similar to those obtained in alkali-dedifferentiated C7F cells, including the acquisition of a fibroblastoid morphology (Fig. 2), reduced cytokeratin expression, increased vimentin expression, and assembly of -smooth muscle actin-containing stress fibers (12).

View larger version (83K): [in this window] [in a new window]   FIGURE 2. Morphology of epithelial mock-transfected Madin-Darby canine kidney-C7 (MDCK-C7) cells (C7Mock1) and MDCK-C7 cells stably transfected with constitutively active MEK1 (C7caMEK1). Phase-contrast micrographs of subconfluent cells are shown. A: flat, polygonal C7Mock1 cells with a typical epithelial phenotype. B: pleiomorphic C7caMEK1 cells, exhibiting spindle-shaped morphology, lack of monolayer formation, and poor adhesion to the culture support. C7caMEK1 cells have lost expression of several epithelial marker proteins such as epithelial cytokeratins and E-cadherin, show formation of -smooth muscle actin-containing stress fibers, and thus represent a dedifferentiated, myofibroblast-like phenotype. Photographs were taken using a Zeiss x 16 objective.

	Signaling node between proliferation and growth arrest

Top Introduction MEK1/2 and their substrates Tissue-specific effects on cell... Signaling node between... Linking ERK1/2 signals to... Conclusions References

 
This idea of cell type-specific differences in the function of the MEK1/2-ERK1/2 signaling module is further supported by results obtained from experiments in fibroblasts. Expression of caMEK1/2 mutants, for example, has been reported to transform fibroblasts and to induce tumor formation in nude mice. Thus stimulation of this intracellular signaling module has not only been linked to alterations of cell differentiation but also to the regulation of cell proliferation. By demonstrating that dominant-negative ERK1 or antisense ERK1 inhibited proliferation of CCL 39 fibroblasts, whereas coexpression of wild-type ERK1 reversed these effects, Pagès et al. (10) were the first to directly show that ERK activation is essential for G₀-arrested fibroblasts to enter the cell cycle. Subsequently, other studies reported that expression of caMEK1 stimulated ERK1/2 and accelerated proliferation, whereas treating cells with MEK inhibitors or transfecting them with active MKP1 inhibited mitogen-induced cell proliferation (Table 1). Together the results suggested that important links between the MEK1/2-ERK1/2 pathway and the cell cycle exist. But how does activation of this signaling module regulate cell proliferation and growth? In fact, MEK1-ERK1/2-driven signals are able to influence cellular growth via several mechanisms (Fig. 3).

View larger version (29K): [in this window] [in a new window]   FIGURE 3. Eukaryotic cell cycle control by the MEK1-ERK1/2 signaling module. The MEK1-ERK1/2 pathway is able to influence cell growth and proliferation via several routes: The ERK group of MAPKs increases the synthesis of pyrimidine nucleotides, stimulates the recruitment of protein-synthesizing ribosomes, modifies transcription factors, and alters the structure of chromatinc. Furthermore, ERK1/2 increases transcription of the cyclin D1 gene and facilitates the formation of active cyclin D1-CDK4 complexes, leading to cell proliferation and growth. Associated with an ERK1/2-dependent persistent induction of the CDK2 inhibitor p21WAF1/Cip1, strong and sustained MEK1-ERK1/2 activation can also induce cell cycle arrest (red arrows). CDK, cyclin-dependent kinase.

Secondly, ERK1 and ERK2 enhance protein translation by increasing the ability of eukaryotic translation factor-4E to recruit the protein-synthesizing ribosomes and other protein synthesis initiation factors to the mRNA (Fig. 3). This effect may be mediated by the phosphorylation of the translation factor by the so-called MAPK-interacting kinase, which itself is activated by ERK1/2.

Also, ERK MAPKs mediate increased cell growth by modification of transcription factors (Fig. 3). ERKs phosphorylate several transcription factors, thereby increasing their transcription rate, which in turn increases the formation of growth-inducing protein products. Moreover, the ERK group of MAPKs may also facilitate gene transcription by altering the structure of chromatin (Fig. 3). ERK1/2 substrates such as Rsk-2 or another MAPK-activated protein, mitogen- and stress-activated protein 1, for example, have been reported to phosphorylate histone H3, histone H1, and high-mobility group-14. Although the exact function of these phosphorylation events is not known, they probably either improve the accessibility of DNA to transcription factors or allow the recruitment of chromatin-modifying enzymes.

Finally, the cell cycle itself is influenced by the MEK1-ERK1/2 signaling module. ERK1/2 increases transcription of the cyclin D1 gene and also facilitates the formation of active cyclin D1/cyclin-dependent kinase (CDK) 4 complexes (Fig. 3). These complexes then phosphorylate the growth-suppressing retinoblastoma protein, leading to the displacement of this protein and histone deacetylases, which results in activation of genes regulated by the transcription factor E2F at the restriction point. E2F promotes the expression of cyclin A and cyclin E in late G₁, which in turn associate with CDK2 and thereby promote growth and DNA replication. In addition, entry into S phase is promoted by proteolytic degradation of the cyclin kinase inhibitor p27^Kip1 in late G₁, contributing to the release from inhibition of the rate-limiting cyclin E-CDK2 complex. Although cyclin E-CDK2 itself contributes to this degradation, a significant component may again depend on ERK activity, which is able to phosphorylate p27^Kip1 in vitro.

In addition to functioning as a positive regulator of cell cycle progression, stimulation of the MEK1-ERK1/2 pathway can also induce cell cycle arrest in fibroblasts. These events are associated with the ERK1/2-dependent induction of the CDK2 inhibitor p21^WAF1/Cip1 (Fig. 3). Induction of p21^WAF1/Cip1 has been reported to occur not only through transcriptional, p53-dependent mechanisms but also through p53-independent mechanisms via ERK activation (11). Although ERK1/2 activation is associated with the induction of both cyclin D1 and p21^WAF1/Cip1, several studies have shown that, in contrast to cyclin D1, the cellular decision to induce p21^WAF1/Cip1 in the G₁ phase of the cell cycle could be largely dictated by the magnitude, rather than the duration, of the ERK1/2 signal (14). Thus a strong and sustained MEK1-ERK1/2 activation could lead to growth arrest via long-term induction of p21^WAF1/Cip1, whereas a biphasic but less robust MEK1-ERK1/2 activation may primarily lead to cell proliferation and growth (Fig. 3). In this respect it is interesting to note that in C7caMEK1 cells we also found an increased cyclin D expression associated with a reduced cell proliferation when compared with mock-transfected cells (8,12). Because we were able to show that MEK inhibition blocks both ERK phosphorylation and cyclin D expression and almost abolishes the already reduced cell proliferation rate of C7caMEK1 cells (8), it is tempting to speculate that the strong activation of MEK1-ERK1/2 in these cells might lead to strong and persistent p21^WAF1/Cip1 expression, thereby attenuating cell cycle progression despite increased cyclin D1 expression.

"...forced activation of ERK1/2...might play a central role at different levels during angiogenesis...."

	Linking ERK1/2 signals to physiological function and disease

Top Introduction MEK1/2 and their substrates Tissue-specific effects on cell... Signaling node between... Linking ERK1/2 signals to... Conclusions References

 
Together these results indicate that MEK1-induced signaling events are important for the cell type-specific regulation of proliferation, growth, and differentiation. But does any evidence exist linking these signaling molecules to human physiology and/or disease? Indeed, increased expression and/or sustained activation of members of the MEK1-ERK1/2 signaling module have been detected in a variety of human tumors, including cancers of breast, lung, colon, pancreas, prostate, and kidney, as well as acute leukemia and malignant gliomas. Furthermore, a highly potent and selective MEK1 inhibitor, which is orally active, suppressed ERK1/2 phosphorylation in colon carcinomas of both mouse and human origin (14). The fact that this compound also inhibited tumor growth and invasiveness in vivo indicates that MEK inhibitors represent a promising, noncytotoxic approach to the clinical management of colon cancer (14). Besides neoplastic diseases, increased ERK2 activation has also been reported in an accelerated heterologous as well as in an autoimmune model of anti-glomerular basal membrane (GBM) antibody-induced crescentic glomerulonephritis (3). In addition, a significant increase in the expression of glomerular MEK1 has been detected in the accelerated form of anti-GBM glomerulonephritis, which is in line with in vitro studies performed in rat glomerular mesangial cells (13), suggesting that elevated MEK1 protein levels might contribute to ERK1/2 activation and could thus be of pathophysiological significance in diseases associated with increased cell proliferation and/or cell transformation in vivo.

Histopathological analyses in a mutant mouse line in which the MEK1 gene has been disrupted by insertional mutagenesis revealed a reduction in vascularization of the placenta that was due to a marked decrease of vascular endothelial cells in the labyrinthine region (6). Furthermore, cell migration assays indicated that MEK1 knockout fibroblasts could not be induced to migrate by fibronectin, although the levels of MEK2 protein and ERK activation were normal. Reexpression of MEK1 in the mutant mouse embryonic fibroblasts restored their ability to migrate. These results suggest that MEK1 is required for a normal response to angiogenic signals that might promote vascularization of the labyrinthine region of the placenta (6). The work of Eliceiri et al. (5) has shown that ERK2 is involved in both angiogenesis and cell migration of vascular endothelial cells and that the sustained activation of this MAPK by integrin-_vß₃ is necessary for angiogenesis. The fact that forced activation of ERK1/2 offers protection from apoptosis, promotes endothelial cell entry into the cell cycle, and induces vascular endothelial growth factor expression by increasing its transcription further indicates that activation of this kinase pathway might play a central role at different levels during angiogenesis (2).

To examine the role that the MEK1-ERK1/2 signaling pathway might play in regulating cardiac hypertrophy in vivo, Bueno et al. (4) generated caMEK1 mice under the control of a cardiac-specific -myosin heavy chain promoter. MEK1 transgenic mice demonstrated concentric hypertrophy without signs of cardiomyopathy or lethality up to 12 mo of age. Moreover, the animals showed a dramatic increase in cardiac function without signs of decompensation over time. caMEK1 transgenic mice and caMEK1 adenovirus-infected neonatal cardiomyocytes each demonstrated ERK1/2 but not p38 or JNK activation, and, in addition, caMEK1 adenovirus-infected cultured cardiomyocytes were partially resistant to apoptotic stimuli. In this context it is of special interest that transgenic mice overexpressing the MAPKKK transforming growth factor-activated protein kinase 1 showed significant p38 activation associated with dilated hypertrophic cardiomyopathy and postnatal lethality (15). Consistent with this report, attempts to generate stable transgenic mice expressing activated forms of MKK6 (which activates p38) or MKK7 (which activates JNK) were unsuccessful because of postnatal lethality associated with dilated cardiomyopathy (4). Together these results indicate that the MEK1-ERK1/2 signaling pathway is able to stimulate a physiological hypertrophy response associated with augmented cardiac function and partial resistance to apoptosis. Stimulation of JNK or p38, on the other hand, might lead to dilative cardiomyopathy and might thus constitute potential targets for pharmacological intervention in this disease state.

	Conclusions

Top Introduction MEK1/2 and their substrates Tissue-specific effects on cell... Signaling node between... Linking ERK1/2 signals to... Conclusions References

 
Together the data obtained so far indicate that the MAPKs ERK1 and ERK2 represent ubiquitous signaling molecules of utmost importance for both human physiology and disease. The MEK1/2-ERK1/2 signaling module is crucial for the cell-type specific regulation of intracellular programs associated with cell differentiation/dedifferentiation/transformation, cell migration/invasion, and cell proliferation and growth. Thus these signaling molecules represent promising targets in a mechanism-based approach to the development of new therapies against different types of cancer. In addition, and depending on stimuli and cellular context, these signals might either govern vascular endothelial cell survival or angiogenetic events during processes as diverse as embryonic development, wound healing, or tumor growth and metastasis. Last but not least, by inducing a beneficial form of cardiac hypertrophy, ERK1/2 activation could serve as an important physiological stimulus that might be advantageous to a failing or dilated myocardium.

	Acknowledgments

 
Because of the journal limit on references, many citations were omitted that would otherwise have been included and that I would like to acknowledge. For a full list of references please write to herbert.schramek{at}uibk.ac.at.

This work is supported by the Austrian Science Foundation.

	References

Top Introduction MEK1/2 and their substrates Tissue-specific effects on cell... Signaling node between... Linking ERK1/2 signals to... Conclusions References

 

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