© 2001 by The Society for Integrative and Comparative Biology
Evolution of Osmosensory MAP Kinase Signaling Pathways1
1 The Whitney Laboratory, University of Florida, 9505 Ocean Shore, Blvd., St. Augustine, Florida 32086
2 Mount Desert Island Biological Laboratory, Old Bar Harbor Road P.O. Box 35, Salisbury Cove, Maine 04672
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 SYNOPSIS INTRODUCTIONMAP KINASE ACTIVATION IN...EVOLUTION OF MAP KINASES...INTEGRATION OF OSMOTIC AND...References |
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Mitogen-activated protein (MAP) kinases constitute a large family of proteins with many functions. They are represented by a multitude of paralogous isoforms in yeast, vertebrates, and other eukaryotes. A phylogenetically conserved function of MAP kinases is to carry osmotic signals from sensory to target elements of cells. Even though this function of MAP kinases is ubiquitous and characteristic of unicellular and multicellular eukaryotes alike the contingencies between individual MAP kinases, sensor elements, and target elements have been subject to vast modification during evolution. Extensive networking of MAP kinase cascades with other signaling pathways is reflected by the large number of diverse signals that can be carried by a single MAP kinase pathway and flexible activation kinetics. It is emerging that the most important function of MAP kinase networks may not be signal amplification but integration of information about the setpoint of environmental parameters (including osmolality) with other physiological processes to control cell function. Insight into how this cellular integration of information is achieved by MAP kinase networks will shed light on the principles of cell dynamics and adaptation.
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INTRODUCTION |
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SYNOPSISINTRODUCTIONMAP KINASE ACTIVATION IN...EVOLUTION OF MAP KINASES...INTEGRATION OF OSMOTIC AND...References |
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Cells are enclosed by a semi-permeable membrane and efficiently maintain an optimal intracellular ionic milieu that supports metabolic activity and cell function. They do this by osmoregulation, i.e., cell volume regulation (Kinne, 2001
), regulation of compatible osmolyte concentration (Yancey, 2001; Ferraris, 2001), adjustment of ion and water transport across the cell membrane (Towle, 2001), and protection of DNA and protein structure (Kültz, 2000). These responses are mediated by osmosensory signal transduction pathways in cells exposed to osmotic stress. MAP kinases are important elements of such pathways in all eukaryotes. The MAP kinase family is one of the largest families of the eukaryotic protein kinase superfamily (Hanks and Hunter, 1995). MAP kinases have undergone an immense diversification during the evolution of eukaryotes reflecting functional multiplicity and the extraordinarily high evolutionary value of this class of proteins. The signature motif [LIVM] [TS] XX [LIVM] XT [KR] [WY] YRXPX [LIVM] [LIVM] is common for all MAP kinases and distinguishes them from other protein kinases (Kültz, 1998). Five distinct MAP kinase subfamilies are found in animals: Extracellular signal-regulated kinase 1 (ERK1), ERK5, stress-activated protein kinase 1 (SAPK1 = JNK), SAPK2 (p38), and MAPK3 (Kültz, 1998). Each of these subfamilies consists of multiple paralogous genes, some of which are expressed as multiple splice variants in mammals and other vertebrates. All MAP kinases are proline-directed serine/threonine kinases that phosphorylate substrates with a proline residue in the P + 1 site of the substrate recognition consensus motif 
X[ST]P, where represents proline or an aliphatic amino acid. MAP kinases are central elements of a conserved core signal transduction module—the MAP kinase cascade—that serves to amplify and integrate extracellular signals at the cellular level (Treisman, 1996). These cascades represent an important intermediate switch between additional signaling elements. The three major elements of MAP kinase cascades are MAP kinase kinase kinases (MAP3K) that phosphorylate and activate MAP kinase kinases (MAPKK), which, in turn, phosphorylate and activate MAP kinases. Important physiological substrates of MAP kinases include transcription factors (Egr-1, c-Jun, ATF2, c-Fos, etc.) and other protein kinases (MAPKAPs, RS6K) that regulate gene expression, protein synthesis/stability, and the cell cycle (Cohen, 1997).
MAP kinases are important mediators of diverse cellular and physiological functions. They are activated by a large variety of extracellular signals, including mitogenic growth factors, cytokines, T cell antigens, pheromones, phorbol esters, UV and gamma irradiation, heat shock, oxidative stress, and osmotic stress. Different MAP kinase subfamilies display varying degrees of responsiveness towards the above stimuli (Kyriakis and Avruch, 1996; Karin, 1996; Woodgett et al., 1996; Ferrell, 1996). For instance, the yeast SAPK (YSAPK) subfamily typified by the high-osmolarity-glycerol response kinase HOG1 is mainly activated during hyperosmolality (Brewster et al., 1993). Other yeast MAP kinase subfamilies (YERK1, YERK2) are predominantly mediators of pheromone responses, cell wall modifications, and mating signals (Gotoh et al., 1993; Gartner et al., 1992; Krisak et al., 1994; Navarro-Garcia et al., 1995).
Of particular interest, the activity of most MAP kinases expressed in animal cells is more or less modulated during osmotic stress. Thus, it is likely that MAP kinases are evolutionary ancient transducers of osmosensory signals. This conjecture is further strengthened by the fact that the physiological capacity for osmosensory signal transduction is a highly conserved function not only of animal MAP kinases but also of certain plant and fungal MAP kinases. In this paper I review the regulation of MAP kinases during osmotic stress, discuss the implications of the evolutionary radiation of MAP kinases, and present new data emphasizing the role of MAP kinases as integrators of primary (direct) and secondary (indirect) osmotic signals.
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MAP KINASE ACTIVATION IN ANIMAL CELLS EXPOSED TO OSMOTIC STRESS |
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The first MAP kinase was discovered in 1987 as a protein kinase capable of phosphorylating microtubule-associated protein, hence the abbreviation MAP kinase (Ray and Sturgill, 1987
). Subsequently, the meaning of this abbreviation was changed to mitogen-activated protein kinase when it became known that mitogenic growth factors are major activators of MAP kinases and when substrates other than microtubule-associated protein were identified (Rossomando et al., 1989; Boulton et al., 1991). These first MAP kinases were members of the ERK1 subfamily. Additional MAP kinase subfamilies have been discovered based on their capacity to confer osmotolerance to diverse organisms. For instance, HOG1 was identified in a genetic screen because it is necessary for yeast to survive hyperosmotic stress (Brewster et al., 1993). The MAP kinase MPK1 (=SLT2), which is necessary for yeast to survive hyposmotic stress was identified by a similar approach (Torres et al., 1991). The first member of the animal SAPK2 subfamily was cloned based on functional complementation of yeast HOG1. Mammalian SAPK2
rescues HOG1-deficient yeast deletion mutants in hyperosmotic medium and restores the osmotolerance of mutant yeast to that of wild-type yeast (Han et al., 1994). Rescue of HOG1 deletion mutants in hyperosmotic medium is also achieved by functional complementation with mammalian SAPK1 (Galcheva-Gargova et al., 1994).
The SAPK1 subfamily of MAP kinases is specific for animals and characterized by a TPY dual phosphorylation motif. In mammals, three isoforms encoded by distinct paralogous gene loci, which are expressed as several alternative splice variants, exist (Gupta et al., 1996). SAPK1 (p54, JNK2) and SAPK1
(p46, JNK1) are ubiquitously expressed in most mammalian tissues. In contrast, SAPK1ß (p49, JNK3) is only expressed in mammalian brain where it may have a role in the pathology of Alzheimers disease (Mohit et al., 1995). SAPK1 and SAPK1 are strongly activated in response to hyperosmolality in many vertebrate cell lines. The activation kinetics in cell culture is always very fast and transient with maximal activation between 5 min and 1 hr following the onset of hyperosmotic stress. In canine MDCK cells we measured that SAPK1 activity is rapidly (maximum at 1 hr) induced in response to the hyperosmotic stress of addition of NaCl to increase the medium osmolality to 600 mosmol/kg H2O (Fig. 1). Rapid hyperosmotic activation of SAPK1 and SAPK1 has also been observed in several other cell types, including rat 3Y1 fibroblasts and PC12 cells (Matsuda et al., 1995), rabbit PAP-HT25 cells (Kültz et al., 1997), and primary rat hepatocytes (Kurz et al., 1998). In murine m-IMCD3 cells maximal activity of SAPK1 and SAPK1 is reached within 1 hr of exposure to hyperosmotic stress of 600 mosmol/kg H2O (Kültz et al., 1998). The activation of SAPK1 in mIMCD3 cells is characteristic for hyperosmotic stress induced by elevated NaCl and mannitol but not by elevations in urea, which readily permeates cell membranes (Zhang and Cohen, 1996; Berl et al., 1997). Hyperosmolality induced by sorbitol, another impermeable solute, activates SAPK1 and SAPK1 in primary cultures of ventricular myocytes from neonatal rat hearts with a maximum at 15–30 min (Bogoyevitch et al., 1995). These results may indicate that changes in cell volume, intracellular electrolyte concentration, or membrane stretch rather than osmotic concentration per se induce SAPK1 activation during hyperosmotic stress. This notion was substantiated in primary cultures of cardiac myocytes from neonatal rat hearts, in which the activity of SAPK1 and SAPK1 increases proportionally to the degree of mechanical stretch with a transient activity peak at 30 min (Komuro et al., 1996). Recent evidence suggests that the effect of membrane stretch and hyperosmolality on SAPK1 activity may be mediated via non-specific clustering of membrane-bound receptors for growth factors and cytokines in the plasma membrane (Rosette and Karin, 1996). In any case, the activation kinetics of SAPK1 is of strong physiological relevance because the duration of SAPK1 activation determines cell fate in response to environmental stress as shown for human Jurkat T cells and 293T embryonic kidney cells (Chen et al., 1996). Thus, the kinetics of SAPK1 activation during hyperosmotic stress may contribute to the outcome of the cellular stress response, i.e., either apoptosis or compensatory adaptation.
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The SAPK2 subfamily of MAP kinases is characterized by a TGY dual phosphorylation motif and confined to animals. Four SAPK2 isoforms that are encoded by distinct paralogous gene loci are expressed in mammals (Kültz, 1998
). All four SAPK2 isoforms have similar molecular masses and migrate as a single band on polyacrylamide gels (p38). The various SAPK2 isoforms are expressed with some degree of isoform-specificity in most mammalian tissues that have been examined. The SAPK2 subfamily of MAP kinases is strongly induced when vertebrate cells are exposed to hyperosmotic stress in the form of NaCl but not urea (Zhang and Cohen, 1996; Kültz and Burg, 1998). Examples include canine kidney MDCK cells (Fig. 1), rat kidney cells (Yoshida et al., 1996), rabbit kidney PAP-HT25 cells (Kültz et al., 1997), murine IMCD3 cells (Berl et al., 1997; Kültz et al., 1998), and human T cells (Junger et al., 1997). The activation kinetics of SAPK2 following onset of hyperosmotic stress is very rapid (e.g., Fig. 1). Because of the very similar molecular mass of all SAPK2 isoforms not much information is available regarding the potency of osmotic stress to induce individual SAPK2 isoforms. SAPK2 and SAPK2ß have similar substrate and inhibitor profiles but are clearly distinct from SAPK2 and SAPK2
in this regard. For instance SAPK2 and SAPK2ß but not SAPK2 and SAPK2 efficiently phosphorylate MAPKAP kinases 2 and 3 and are potently inhibited by pyridinyl imidazole compounds such as SB203580 (Cuenda et al., 1997; Goedert et al., 1997; Cohen, 1997). Moreover, only SAPK2 but not SAPK2ß is able to complement HOG1 in yeast deletion mutants (Kumar et al., 1995). These differences are likely physiologically relevant and suggest different roles of individual SAPK2 isoforms during osmotic stress. However, this conjecture remains to be tested.
The third major animal MAP kinase subfamily, ERK1, is also regulated during osmotic stress even though most studies have concentrated on investigating its regulation by mitogenic growth factors. ERK1 is characterized by a TEY dual phosphorylation motif. Many mammalian cell lines, including canine kidney MDCK cells (Fig. 1; Itoh et al., 1994; Terada et al., 1994), H4IIE rat hepatoma cells (Schliess et al., 1997), and murine kidney mIMCD3 cells (Kültz et al., 1998) respond to hyperosmolality by rapid induction of ERK1. This induction is shown by both ERK1 isoforms, ERK1 (p44) and ERK1ß (p42). In contrast to SAPK1 and SAPK2, ERK1 is also induced if the hyperosmolality is due to increased urea (Cohen, 1999). In this case, osmotic regulation of transcription of the immediate early gene Egr-1 is mediated in part through 5'-flanking regions containing serum response elements and adjacent Ets motifs, and in part through the minimal Egr-1 promoter (Zhang et al., 1998). The kinetics of ERK1 activation is different from SAPK1 and SAPK2 in that it is very transient and almost completely abolished within 1 hr (Fig. 1). In fact, ERK1 induction during hyperosmotic stress seems to be suppressed by a negative feedback from SAPK2 in murine kidney IMCD3 cells (Kültz et al., 1998). This negative feedback mechanism may be responsible for the very short period of increased ERK activity following hyperosmotic shock. Even though most studies concerning the effects of osmotic stress on SAPK1, SAPK2, and ERK1 have been conducted by exposing cultured mammalian cell lines to hyperosmotic shock, hyposmotic stress as well has been shown to induce these MAP kinases in various cell types (Sadoshima et al., 1996; Schliess et al., 1996; Tilly et al., 1996; Sinning et al., 1997; Zhang et al., 1998).
Besides the three MAP kinase subfamilies discussed above, two additional MAP kinase subfamilies, ERK5 and MAPK3, occur in animals (Kültz, 1998). The regulation of MAPK3 during osmotic stress has yet to be investigated. ERK5 is induced in rat vascular smooth muscle cells exposed to hyperosmolality (Abe et al., 1996). The robust osmotic regulation of many MAP kinases suggests that they are essential and highly conserved components of osmosensory signal transduction pathways in eukaryotic cells. The following is a brief analysis of the evolutionary radiation of the MAP kinase family with emphasis on the significance of multiple paralogous MAP kinase isoforms for osmotic stress signaling.
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EVOLUTION OF MAP KINASES FROM LOWER TO HIGHER EUKARYOTES |
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MAP kinases occur in all eukaryotes but have not been found in prokaryotes. All currently known MAP kinases of protozoans, which are phylogenetically very primitive eukaryotes, belong to the MAPK3 subgroup and contain TEY or TDY dual phosphorylation motifs (Kültz, 1998
). Most of these protozoan MAP kinases have a conserved primary structure but unusually long, variable carboxy-terminal tails suggesting that they descended early from a common ancestral MAPK (Hua and Wang, 1994; Doerig et al., 1996; Lin et al., 1996; Kültz, 1998). Thus, the investigation of osmotic effects on the activity of protozoan MAP kinases would provide a good indication as to whether primitive MAP kinases were already used for osmosensory signal transduction. Unfortunately, data on the osmotic regulation of protozoan MAP kinases are still lacking. MAPK3 is not unique for protozoans but members of this MAP kinase subgroup have also been cloned from yeast (Segall et al., 1995), invertebrates (Fig. 2), and vertebrates (Robbins et al., 1993; Zhu et al., 1994; Fig. 2). Because the MAPK3 subgroup and the ERK subgroup, which includes animal ERK1 and ERK5 (Fig. 2), yeast ERK (YERK1 and YERK2) and plant ERK (PERK) subfamilies, both contain TEY dual phosphorylation motifs it is likely that a common ancestor for ERK and MAPK3 subgroups existed before protozoans and slime molds diverged from the phylogenetic lineage from which plants, fungi, and animals originated. I already pointed out that animal ERK1 and ERK5 subfamilies are osmotically regulated (see above). In addition, the activity of fungal and plant ERKs is also regulated during osmotic stress (Kültz and Burg, 1998). In Schizosaccharomyces pombe, the ERK isoform MPK1 is activated in response to hyposmotic stress and part of a cell wall integrity pathway (Ruis and Schüller, 1995). Homologous ERKs are osmotically regulated in Saccharomyces cerevisiae (SLT2, Torres et al., 1991) and Candida albicans (MKC1, Navarro-Garcia et al., 1995). Of interest, the plant ERK MMK2 cloned from Medicago sativa is able to functionally complement yeast MPK1 deletion mutants during hyposmotic stress (Jonak et al., 1995). Several other plant ERKs are also regulated by osmotic stress, including MMK4 in Medicago sativa (Jonak et al., 1996), ATMPK3 in Arabidopsis thaliana (Mizoguchi et al., 1996), and PsMAPK in Pisum sativum (Popping et al., 1996). PsMAPK has been shown to rescue S. cerevisiae HOG1 deletion mutants in hyperosmotic medium (Popping et al., 1996). This suggests that plant ERKs have evolved the capacity to function in osmosensory signal transduction pathways that are not controlled by ERK but by the SAPK subgroup in animals and yeast, thereby compensating for the lack of plant SAPKs (Kültz and Burg, 1998). Because of the generality of the osmotic responsiveness of animal, yeast, and plant MAP kinases it seems likely that their common ancestor had a role in osmosensory signal transduction, which conferred an evolutionary advantage to eukaryotes leading to natural selection of this trait. This conjecture is consistent with the importance of osmotic stress as a ubiquitous and major selection pressure during the evolution of life (Kültz and Csonka, 1999). However, an important piece of evidence that would validate this hypothesis has yet to be provided: experimental evidence for the osmotic regulation of the MAPK3 subgroup.
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ERKs underwent an extensive evolutionary radiation starting already before multicellular eukaryotes emerged. The third MAP kinase subgroup, stress-activated protein kinases (SAPKs), was also subject to extensive evolutionary radiation but much later than ERKs. The radiation of SAPKs seems to be based on multiple gene duplication events and correlated with the diversification of metazoan phyla, which peaked in the cambrium, ca. 500 million years ago. Only a single SAPK gene is present in yeast compared to at least two SAPK1 and two SAPK2 genes in the nematode Caenorhabditis elegans and the fly Drosophila melanogaster (Fig. 2). Mammals have at least seven SAPK genes, three for SAPK1 and four for SAPK2 (Fig. 2). Because of the lack of more comparative data it is currently not certain whether the evolutionary radiation of SAPKs reached its peak in mammals or, alternatively, gave rise to the origin of more than seven SAPK genes in certain animal taxa. The emerging field of comparative genomics will undoubtedly generate a better understanding of when major SAPK gene duplication events took place. In any case, it is likely that the ancestral SAPK was similar to that of yeast SAPK. This ur-SAPK gene was apparently lost or extensively modified in plants, maintained in fungi, and subject to several rounds of gene duplication events in metazoans. Yeast SAPK, best known under the name HOG1 (high osmolarity glycerol response kinase), is characterized by a TGY dual phosphorylation motif and most similar to the animal SAPK2 subfamily (see above). A complete biochemical pathway centered on HOG1 and connecting primary osmosensors with osmoregulated genes has been elucidated (Wurgler-Murphy and Saito, 1997
). This osmosensory signal transduction pathway was first discovered in S. cerevisiae (Brewster et al., 1993) and subsequently shown to also exist in other fungi (San Jose et al., 1996; Aiba et al., 1995). The HOG pathway is induced during hyperosmolality as follows: At normal osmolality, the osmosensor SLN1, which is a transmembrane protein, is constitutively active as an aspartate kinase. SLN1 is the sensor kinase component of a two-component system controlling the phosphorylation status of the response regulator SSK1. In addition, the SLN1-SSK1 two-component system contains an intermediate phospho-relay protein YPD1 (Posas et al., 1996). Constitutive phosphorylation on aspartate by SLN1 activates SSK1, which, in turn, inhibits two redundant MAP3Ks, SSK2 and SSK22. These MAP3Ks control the activity of the MAPKK PBS2, which phosphorylates and activates HOG1. Therefore, HOG1 is inactive at normal osmolality. During hyperosmolality the osmosensor SLN1 autophosphorylates on a histidine residue and its aspartate kinase activity is inhibited leading to activation of HOG1. The alternative osmosensor SHO1 can regulate the HOG pathway independent of the SLN1/SSK1 two-component system (Wurgler-Murphy and Saito, 1997). Two-component systems are classical modules of signal transduction in prokaryotes that have also been found in yeast and plants but not in any animal. Thus, during the evolution of metazoa two-component systems may have been lost and new contingencies centered on alternative osmosensors such as SHO1 or novel, as yet unknown, osmosensory elements may have developed as upstream-regulators of MAP kinase cascades. It is likely that the development of novel SAPK-dependent signal transduction contingencies proceeded in parallel to the radiation of SAPKs in animals. In this regard it is interesting that many vertebrate SAPKs are major transducers of immune response-related and cytokine-reponsive signals. Therefore, the origin of a system of acquired immune response of vertebrates might have been contingent upon the radiation of SAPKs, resulting in novel and more complex signal transduction networks that retained conserved signaling functions such as osmosensing, yet are able to compute a large number of additional signals. In summary, the evolution of MAP kinases into diverse subfamilies reflects an aquirenment of additional signaling functions and complexity. However, the degree of this diversification differs greatly in different taxa of eukaryotes and was restrained by the necessesity to retain vital signaling functions that already existed in the progenitor of all MAP kinases, the ur-MAP kinase. Osmosensory signal transduction is very likely one of those ancient vital functions because it is conserved in most extant MAP kinases. Another such vital function of ur-MAP kinases was likely the modulation of the cell cycle but a discussion of MAP kinase functions in cell cycle control exceeds the scope of this paper. An interesting task of future research concerns the structure and function of MAP kinases of lower metazoans such as sponges and cnidarians. The detailed study of such MAP kinases would provide valuable data for tracing the early evolution of animal MAP kinase subfamilies. In addition, protozoan MAP kinases, representing a phylogenetically ancient type of MAP kinases, hold valuable clues for deciphering basic and evolutionary conserved contingencies of MAP kinase-dependent cellular signal transduction.
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INTEGRATION OF OSMOTIC AND OTHER SIGNALS BY MAP KINASES |
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Osmosensory signal transduction is but one function of MAP kinases, which are involved in a great variety of additional signaling functions. These include the onset of programmed cell death (apoptosis), cell cycle modulation, the regulation of cell integrity and cell growth, modifications of the cytoskeleton and cell shape, induction of cell division, cell differentiation, and various cellular adaptations to environmental stress (Kyriakis and Avruch, 1996
; Woodgett et al., 1996; Davis, 1994; Treisman, 1996; Karin, 1996). Even though many paralogous MAP kinases are expressed in a single yeast or vertebrate cell their number alone cannot account for this great diversity of signaling functions. Each MAP kinase cascade can be activated by multiple sensory elements and targets multiple effectors. The physiological targets of MAP kinase cascades differ depending on the initial stimulus that serves as the activating signal. In addition, MAP kinase cascades are able to reinforce or dampen their own induction depending on the nature of the initial stimulus (Nishida and Gotoh, 1993). MAP kinase cascades can be viewed as core signaling units that bundle sensory information, subject it to regulatory and integrative feedback, and, based on such feedback, disperse it to a defined array of response elements. In this sense, MAPKKs are convergence points (elements for branched signal input) whereas MAP kinases are divergence points (elements for branched signal output). The physiological significance of this arrangement is not entirely clear but it may be necessary to integrate a large number of different stimuli with a minimum number of proteins. After all, cells are limited in the number of different protein species that can be expressed simultaneously, on average ca. 10,000 in a differentiated vertebrate cell (Kültz and Somero, 1996). Most of these proteins have multiple functions and we know that MAP kinase cascades are not just linear pathways but represent complex signaling networks that are subject to many contingencies. For example, a particular MAP kinase cascade can not only reinforce or dampen their own induction but also that of other MAP kinase cascades. This is achieved in part by modulation of the activity of MAP kinase phosphatases (Bokemeyer et al., 1996; Degols et al., 1996; Muda et al., 1996; Brondello et al., 1997; Hirsch and Stork, 1997; Jacoby et al., 1997). Cross-talk between multiple MAP kinases has indeed been observed as part of the osmotic stress response of several mammalian cell lines (Schliess et al., 1997; Kültz et al., 1998). It is important to realize that MAP kinase cascades are not just linear arrangements but integral parts of complex signal transduction networks that are necessary to compute cellular functions based on unique combinations of signals and modulatory factors. In reality, many of such input elements act on cells simultaneously and not in an isolated fashion.
The most complete picture of cellular MAP kinase signaling is known from single-celled eukaryotes, mainly budding and fission yeast. In yeast, many MAP kinase isoforms are present but they represent distinct subfamilies compared to vertebrates (Kültz, 1998). The evolutionary radiation of MAP kinases in yeast reflects an optimization of cellular signal transduction driven by the special needs of a sophisticated and well-adapted unicellular organism. Many essential functions of yeast are contingent on MAP kinase signaling, including the response to pheromones, cell cycle regulation, mating and meiosis, cell growth (in particular, infectious growth), cell polarization, and cell wall integrity (Gartner et al., 1992; Gotoh et al., 1993; Xu and Hamer, 1996; Mazzoni et al., 1993; Krisak et al., 1994; Navarro-Garcia et al., 1995). Notably, some of these functions are uniquely important for unicellular eukaryotes and have little significance for most cells of metazoans. But even in primitive unicellular eukaryotes MAP kinase pathways are extensively networked and each MAP kinase cascade is utilized for multiple distinct functions. To illustrate this important point I will again consider the yeast SAPK (HOG) osmosensory MAP kinase cascade again. In budding yeast, S. cerevisiae, the MAP kinase (HOG1) and MAPKK (PBS2) are the only two components that are common core elements of the HOG pathway. At least two distinct mechanisms activate PBS2: (1) the SLN1-SSK1-SSK2/22 branch and (2) the SHO1-STE11 branch (Posas and Saito 1997; see above). In addition, STE50 is a mandatory coactivator of STE11 in the latter branch (Posas et al., 1998). The convergence of two distinct upstream pathways at the level of MAPKKs is a common feature of animal cells. As outlined above, the main function of the HOG cascade is to transduce information about the setpoint of environmental osmolality. However, this is not its only function. The MAP3K STE11 also activates the pheromone response pathway via the STE11-STE7-FUS3/KSS1 MAP kinase cascade (Ruis and Schüller, 1995). Recent experimental evidence supports the existence of a negative feedback mechanism by which HOG1 and PBS2 inhibit the pheromone response pathway (O'Rourke and Herskowitz, 1998). These authors discovered that HOG1 and PBS2 mutations allowed osmolarity-induced activation of the pheromone response pathway that depended on a functional SHO1 osmosensor, as well as STE20, STE50, the pheromone response MAPK cascade (STE11, STE7, and FUS3/KSS1), and STE12. STE20 and STE50 both function in the SHO1 branch of the HOG pathway and yet another osmosensor distinct from SHO1 and SLN1 may activate STE11 via STE12 (O'Rourke and Herskowitz, 1998). In addition, pseudohyphal growth depends on SHO1, suggesting that SHO1 is not exclusively an osmosensor but also a receptor for pseudohyphal growth signaling (O'Rourke and Herskowitz, 1998). Of interest, NIK1 of Candida albicans, which is a homologue of the osmosensor SLN1 that controls the SHO1-independent branch of the HOG pathway in S. cerevisiae, is also involved in hyphal morphogenesis and responsible for certain virulence properties of the organism even though it is structurally completely unrelated to SHO1 (Alex et al., 1998). Thus, the HOG pathway is subject to extensive signal integration and feedback regulation resulting in diverse signaling functions that depend on the sum of environmental stimuli at any given time. In fission yeast, Schizosaccharomyces pombe, the SPC1 pathway is homologous to the S. cerevisiae HOG pathway and contains the MAPKK WIS1 and the MAP kinase SPC1. The SPC1 pathway is required for survival in hyperosmotic medium and induction of mitosis (Shiozaki et al., 1997). SPC1 also interacts with and alters the function of STS5, a regulator of cell shape during polarized growth. SPC1 is not only activated in response to hyperosmotic stress but also many other forms of environmental stress, including high temperature and oxidative stress (Degols et al., 1996). The SPC1 cascade links environmental signals with mitotic control but is also important for sexual development and meiosis (Shiozaki and Russell, 1996). Nitrogen limitation, a key signal for the promotion of fission yeast conjugation, activates SPC1 resulting in the phosphorylation of the transcription factors ATF1 and ATF2 (Shiozaki and Russell, 1996). However, ATF1 phosphorylation leading to its activation only induces meiotic and stress-response genes but not mitosis-regulatory genes indicating a bifurcation of signal transduction at SPC1 into mitotic and meiotic/stress response pathways (Shiozaki and Russell, 1996). This is consistent with a role of MAP kinases as divergence points of cellular signal transduction (see above). Thus, even in primitive unicellular eukaryotes MAP kinase pathways are utilized for the integration of multiple signals. Cross-talk between different MAP kinase pathways and between MAP kinase cascades and other signaling pathways represents an important element of MAP kinase function in addition to mere signal amplification.
Multicellular eukaryotes have other subfamilies of MAP kinases than unicellular eukaryotes (Kültz, 1998). Plant MAP kinases all belong to a single subfamily (plant ERKs) and vertebrate MAP kinases are distributed among at least 5 subfamilies (Fig. 2). The evolution of new MAP kinase subfamilies in plants and metazoans likely reflects a modification of MAP kinase function due to the evolutionary pressure to fit novel needs arising from multicellular organization. Multicellularity requires many specializations of cell function, which depend on the generation of new contingencies evolving around MAP kinases cascades and other core signaling modules. Cell functions specific to multicellular organisms include cell-cell communication, programmed cell death (apoptosis), cell-type specific differentiation, cell-mediated immune responses, coordination of cell growth within a particular tissue or organ, coordination of adaptive responses of cells, and homeostasis of intercellular space. These special functions depend to a large extent on highly sophisticated signal transduction networks, of which MAP kinases are core units. Much valuable information on MAP kinase function has been gathered from work using mammalian cell lines and these valuable models will continue to provide critical information regarding the function of MAP kinases in vertebrate cells. However, cells cultured in vitro may have altered growth patterns, physiological functions, survival mechanisms, cell-cell communication, mechanisms of senescence and cell death, differentiation patterns, and adaptive responses. In short, there is considerable evidence that cell cultures have lost some key features of multicellular organization. They may not respond like cells in vivo to a particular stimulus such as osmotic stress that activates MAP kinases. In contrast to yeast it has proved difficult to identify physiologically significant targets of MAP kinases during osmotic stress in animal cell cultures. Currently, there is contradictory evidence regarding the role of MAP kinases for the activation of osmoprotective genes encoding enzymes and transporters regulating the levels of compatible organic osmolytes (Kwon et al., 1995; Kültz et al., 1997; Berl et al., 1997; Sheikh-Hamad et al., 1998; Wojtaszek et al., 1998a; Nadkarni et al., 1999). These genes are osmotically regulated via tonicity/osmotic responsive enhancer elements (TonE/ORE), which are distinct from the stress response elements that are targeted by MAP kinases in yeast (Ferraris, 2001; Table 1). In addition, the transcription factors activated by yeast HOG1 (MSN2/4) are completely different from the transcription factor activating the mammalian TonE/ORE (Martinez-Pastor et al., 1996; Miyakawa et al., 1999). Currently, our efforts focus on identifying the physiological targets and the in vivo significance of MAP kinase activation during osmotic stress in mammalian and other vertebrate cells. We have measured in vivo responses of MAP kinases under physiological conditions in intact fish brain (Fig. 3). The brain of vertebrates contains systemic osmosensors that monitor plasma osmolality. They respond to a deviation from osmotic homeostasis by the activation of neural and hormonal signals that restore osmotic homeostasis by regulating ion and water transport across osmoregulatory tissues (McCormick, 2001; Evans, 1993). We measured dual phosphorylation on the TXY activation motif as an indicator of the activity of three MAP kinases during sudden salinity transfer of the euryhaline teleost Fundulus heteroclitus (Fig. 3). SAPK1 (p45) activity in whole brain extracts is not changed during transfer of fish from seawater (SW) to fresh water (FW) and vice versa (Fig. 3a). On the contrary, the activity of SAPK2 (p43), and ERK1 (p46) significantly increase during hyposmotic stress (SW 
FW transfer) and significantly decrease during hyperosmotic stress (FW SW transfer) (Fig. 3b, c). The increase in MAP kinase activity observed during hyposmotic stress in F. heteroclitus brain is consistent with MAP kinase activation observed in vitro in animal cell lines. However, hyperosmotic stress also leads to activation of MAP kinases in cell culture whereas it causes MAP kinase inhibition in F. heteroclitus brain in vivo. Another important difference concerns the kinetics of MAP kinase activation following osmotic stress in vivo vs. in vitro. Osmotic regulation of MAP kinase activity in cultured vertebrate cells is always transient, with a peak at 5 min–1 hr and declines to baseline levels within 6–24 hr (see above). Figure 3 illustrates that osmotic regulation of MAP kinase activity in F. heteroclitus brain in vivo is not transient but rather stable. This is not a peculiarity attributable to fish brain only but has also recently been observed in the rat renal papilla (Wojtaszek et al., 1998b). As outlined above, the activation kinetics of MAP kinases determines cell fate and the outcome of the cellular stress response—either apoptosis or compensatory adaptation. Thus, the difference in MAP kinase activation kinetics observed in vitro vs. in vivo may underlie the altered senescence behavior and higher osmotic tolerance thresholds of animal cells in vitro compared to in vivo. This difference in osmotic MAP kinase regulation likely reflects the lack of indirect osmotic signals (neural, hormonal) in cell cultures. These signals act on cells in vivo and are known modulators of MAP kinase function. The lack of these modulators in cell cultures may lead to an altered integration of signals by MAP kinases reflected in different activation kinetics.
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In conclusion, an emerging general paradigm from experiments on yeast, vertebrate cell cultures, plants, and whole animals is the tight interrelationship of MAP kinase functions for the environmental (osmotic) stress response and cell cycle regulation/growth control. In the future it will be important to investigate the physiological roles of individual isoforms of MAP kinases in the osmotic stress response of animal cells, analyze the osmotic responsiveness of the MAPK3 subgroup in animals and protozoans, analyze the MAP kinase isoform pattern in primitive metazoans, and elucidate the biochemical nature of cross-talk between MAP kinase cascades and other pathways. These experiments will shed light on how MAP kinase networks compute osmosensory information in cells and how this capacity is integrated with other important cell functions.
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ACKNOWLEDGMENTS |
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I would like to thank Ms. Kristina Avila for technical assistance during the experimental analysis of MAP kinase responses in fish brain. This work was supported by a pilot project grant funded by the Howard Hughes Research Resources Program (HHRRP #571360212), the Whitney Laboratory, and the Salisbury Cove Research Fund of the MDIBL.
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FOOTNOTES |
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1 From the Symposium Osmoregulation: An Integrated Approach presented at the Annual Meeting of the Society for Integrative and Comparative Biology, 4–8 January 2000, at Atlanta, Georgia.
2 E-mail: dkkw{at}whitney.ufl.edu
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