Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA
Author for correspondence (e-mail: Elaine_elion{at}hms.harvard.edu)
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SUMMARY |
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Key words: Scaffold, MAP kinase, Signal transduction, RING-H2 domain, S. cerevisiae, Mating
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Introduction |
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The first MAPK scaffold to be described was the yeast Ste5 protein (i.e. Ste5p) (Kranz et al., 1994; Choi et al., 1994; Marcus et al., 1994; Printen and Sprague, 1994), which associates with G protein, MAPKKK, MAPKK and MAPK of the mating pathway (Fig. 1). Since its discovery, a number of analogs of Ste5p have been described in yeast (Fig. 2) and mammals (Burack and Shaw, 2000; Whitmarsh and Davis, 1998). Here, I describe the multiple functions of Ste5p in the regulation of a MAPK cascade and emphasize the growing evidence that Ste5p does not play a passive role in signal transmission, highlighting its important role in spatiotemporal localization of a MAPK cascade to a G protein at the plasma membrane.
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Overview of the mating MAPK cascade and identification of Ste5p |
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Many of the components of the mating MAPK cascade are used in other MAPK cascades. Ste20p (the MAPKKKK) and Ste11p (the MAPKKK) are used in the high-osmolarity/glycerol (HOG) pathway to help cells survive osmotic stress (Gustin et al., 1998; ORourke and Herskowitz, 1998). Ste20p and Ste11p are also used with the MAPKK Ste7p and MAPK Kss1p in both the invasive growth and pseudohyphal development pathways to promote food uptake during nutrient deprivation in haploids and diploids (Liu et al., 1993; Roberts and Fink, 1994) and in the sterile vegetative growth (SVG) pathway that promotes cell wall integrity (Lee and Elion, 1999). In these pathways, Kss1p is the key MAPK; the MAPK Fus3p does not have a positive regulatory role, but it inhibits both invasive growth and SVG pathways in its inactive form (Madhani et al., 1997; Lee and Elion, 1999). Pathway specificity is gained through the use of Fus3p, which is used solely by the mating MAPK cascade (Madhani and Fink, 1997) and is expressed only in haploids, the type of cell that mates (Elion et al., 1990). However, the use of Fus3p does not fully explain pathway specificity, because MAPK Kss1p is efficiently activated by mating pheromone in wild-type cells regardless of whether it is overexpressed (Gartner et al., 1992; Ma et al., 1995) or whether it is present at native levels (Cherkasova and Elion, 2001). Additional specificity is thought to be provided by the Ste5p scaffold, which is solely required for the mating MAPK cascade pathway and is expressed only in haploid cells.
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Genetic identification of Ste5p and its placement in the MAPK cascade |
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Further genetic observations indicated that Ste5p function could not be defined in simple linear terms in a signal transduction pathway. These genetic studies suggested that Ste5p plays a complicated role in signaling and functions at multiple steps in the pathway to activate MAPK Fus3p (Kranz et al., 1994; Elion, 1995). Additional work indicated that Ste5p overexpression enhances Fus3p kinase activity and that Ste5p physically associates with and is phosphorylated by Fus3p and additional associated kinase(s) in vivo (Kranz et al., 1994). These and other observations suggested that Ste5p positively regulates the activity of Fus3p by interacting with multiple signal transduction components required for its activation.
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Defining Ste5p as a MAPK cascade scaffold |
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Further evidence argues that the association between Ste5p and the MAP kinases is a regulatory one that leads to activation of the MAPK Fus3p. Ste5p is rate limiting for activation of Fus3p (Kranz et al., 1994), and Fus3p has its highest specific activity in the 350-500 kDa glycerol gradient fractions that also contain Ste5p, Ste11p and Ste7p (Choi et al., 1999). The Ste5p-multikinase complex is detected before pheromone stimulation, especially when the kinases are inactive mutants (Choi et al., 1994). Ste5p enhances the ability of Ste11p and Ste7p to associate (Choi et al., 1994; Marcus et al., 1994) but does not appear to influence the ability of Ste7p to associate with the MAPKs (Choi et al., 1994; Marcus et al., 1994; Printen and Sprague, 1994). In addition, Ste5p preferentially co-precipitates hypophosphorylated forms of Ste7p, which are thought to represent pre-activated molecules that have not yet undergone feedback phoshorylation by Fus3p (Choi et al., 1994). These findings led to the proposal that Ste5p tethers Ste11p to a Ste7p-Fus3p dimer that dissociates upon phosphorylation of Ste7p by Fus3p (Choi et al., 1994). Subsequent work supports this model and argues that Ste7p and Fus3p form stable complexes independently of Ste5p (Bardwell et al., 1995) and that the binding of Ste5p to Ste11p and Ste7p is required for signal transmission (Inouye et al., 1997a; Bardwell et al., 2001).
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Defining an activation function for Ste5p that is distinct from scaffolding |
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Several lines of evidence first hinted that the binding of Ste5p to Ste11p is essential for its activation by mating pheromone. Ste5p is required for the full basal activity of hyperactive Ste11p mutants, whereas the Gß subunit Ste4 is not (Stevenson et al., 1992; Elion, 1995). Ste5p associates with the N-terminal regulatory domain of Ste11p (Choi et al., 1994; Marcus et al., 1994; Printen and Sprague, 1994), and a larger percentage of Ste11p co-sediments with Ste5p in a glycerol gradient than with Ste7p or Fus3p (Choi et al., 1994). In addition, co-overexpression of Ste5p with Ste11p causes synergistic activation of Fus3p in the absence of pheromone (Choi et al., 1994). More recent studies in fact suggest that Ste5p plays two roles in the activation of Ste11p: (1) localization of Ste11p to the MAPKKKK Ste20p at the cell cortex; and (2) allosteric control of Ste11p or the other associated kinases.
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Ste5p recruitment to Gß![]() |
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Additional findings strongly support the view that the Gß subunit of the Gß dimer (comprising Ste4p and Ste18p) recruits both Ste20p and Ste5p in the presence of pheromone and that these interactions are required for Ste20p to activate Ste11p (Fig. 2). First, the need for Ste4p and Ste18p can be bypassed by artificially targeting Ste5p to the plasma membrane using a C-terminal transmembrane domain (Pryciak and Huntress, 1998). Plasma-membrane-targeted Ste5p, with or without the first 214 residues that overlap the Ste4p-binding domain, constitutively activates the pathway, but only if Ste20p is present; this is strong evidence that Gß
must recruit Ste5p in parallel to Ste20p activating Ste11p (Pryciak and Huntress, 1998). The Gß
dimer appears to bind to a pool of Ste20p that is already at the cell cortex, owing to its interaction with Cdc42p-GTP, because this interaction is required for efficient signal transmission induced by the Gß subunit Ste4p (Moskov et al., 2000). In contrast, Ste5p appears to be rapidly recruited to the plasma membrane by the pheromone stimulus (Mahanty et al., 1999). Translocation of Ste5p to the plasma membrane can be detected within a few minutes of pheromone addition in the presence of cycloheximide, which is consistent with a rapid recruitment event that would be needed for pathway activation. In co-precipitation tests, Ste5p recruits Ste11p, Ste7p and Fus3p to the cortical protein Bem1p (Lyons et al., 1996), which provides biochemical support for the idea that in vivo Ste5p recruits the kinases to targets. Thus, Ste5 appears to play an important spatial role assembling the kinases at Gß
dimers at the plasma membrane. Currently, it is not known whether Ste5p forms a stable anchoring structure at the plasma membrane upon which the enzymes assemble, are activated and disassemble. However, the fact that membrane-targeted Ste5p can promote nuclear responses such as transcription (Pryciak and Huntress, 1998) argues that, once activated, Fus3p dissociates and translocates to the nucleus.
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Oligomerization and conformational changes |
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Ste5p might translocate to Gß (Ste4p and Ste18p) as a dimer or as an oligomer that binds to the kinases. Ste5p oligomerization occurs constitutively and is not influenced by mating pheromone (Feng et al., 1998); it might therefore occur before binding to Gß
. In addition, mutating the RING-H2 domain simultaneously interferes with its ability to oligomerize and associate with Gß
(Feng et al., 1998). In a glycerol gradient, the fraction of Ste5p that co-sediments with Ste11p, Ste7p and Fus3p has an estimated mass of 350-500 kDa (Choi et al., 1994), a size that is consistent with a Ste5p dimer associated with two molecules each of Ste11p, Ste7p and Fus3p, and the interactions within this complex occur independently of pheromone (Kranz et al., 1994; Choi et al., 1994). MAPKs form stable dimers (Cobb and Goldsmith, 2000), but this has not been demonstrated for Fus3p. However, the available evidence suggests that Ste11p forms dimers (Printen and Sprague, 1994; Rad et al., 1998). Thus, a large complex consisting of a Ste5p dimer and two molecules each of Ste11p, Ste7p and Fus3p might translocate en masse to the plasma membrane.
Additional unsolved issues are how does Ste5p regulate the activity of the associated kinases and does it directly control kinase activity. Several lines of indirect evidence led to the suggestion that Ste5p positively regulates the activity of the associated kinases independently of its ability to recruit them to Ste20p at the plasma membrane (Elion, 1995; Lyons, 1996; Feng, 1998). A hyperactive Ste11-4p mutant that has significantly elevated basal activity requires Ste5p for 98% of this signaling capacity but does not require Ste4p (the Gß subunit) (Stevenson et al., 1992) or Ste20p (Feng et al., 1998). In addition, Ste5p can promote the activation of the MAPK cascade in the absence of Ste20p (Lyons et al., 1996) and stimulate basal activity of Ste11-4p when it is unable to bind to Ste4p (Feng et al., 1998). Recent work strongly argues that Ste5p directly regulates the activity of the associated kinases by undergoing conformational changes (Sette et al., 2000). Three Ste5-GST gain-of-function mutants that stimulate Ste20p-dependent basal signaling when overexpressed in the absence of Ste4p and a functional RING-H2 domain have been isolated and characterized. Two of the mutations enhance the ability of full-length Ste5p to associate with the N-terminal half of Ste5p - the strength of the effect on binding correlating with the increase in basal signaling (Sette et al., 2000). These results led to the interesting proposal that Ste5p exists as either a folded dimer of parallel strands or as a dimer of anti-parallel strands, and that the binding of the Gß dimer alters the conformation of either closed structure in such a way that Ste20p, Ste11p, Ste7p and Fus3p are optimally aligned for serial phosphorylation (Fig. 3).
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An oligomerization model for recruitment |
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An alternative model that reconciles these (Feng et al., 1998; Mahanty et al., 1999) and other data (Lyons et al., 1996; Yablonski et al., 1995; Inouye et al., 1997b) proposes that Ste5p exists in two forms: a less active, folded or closed monomer or dimer in which the RING-H2 domain is not available to bind Gß and basal signaling is repressed (Fig. 4A); and an open, active dimer of parallel strands (Fig. 4B) in which the RING-H2 domain binds to Gß
and interactions involving the N- and C-termini drive the formation of head-to-tail multimers (Fig. 4C). In this model, the binding of the RING-H2 domain to Gß
would be predicted to block intramolecular interactions between the N- and C-termini and open the folded structure, driving head-to-tail multimerization of adjacent Ste5p dimers. This event might cause a global rearrangement that could position the kinases for recognition by Ste20p. Moreover, simple concentration of the kinases by multimerization of Ste5p might also be sufficient to help drive activation of the MAPK independently of any contribution by Gß
and Ste20p (Robinson et al., 1998; Kieran et al., 1999).
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Nuclear shuttling of Ste5p and links to pathway activation |
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The available evidence suggests that nuclear shuttling controls the amount of Ste5p that is available to bind to Gß. Overexpression of Ste5p is sufficient to activate Ste11p (the MAPKKK) in the absence of pheromone (Choi et al., 1994), which suggests that the access of Ste5p to Gß
must be carefully controlled. Hyperactivation of Ste11p is lethal, presumably because of its participation in multiple MAPK cascades. Enhanced nuclear shuttling correlates with better recruitment and pathway activation (Mahanty et al., 1999) (Y. Wang and E.A.E., unpublished data), which suggests that this regulatory device controls how much Ste5p is available to bind to Gß
. Indeed, partial blocking of reimport of Ste5p enhances the activity of the pathway (Mahanty et al., 1999; Kunzler et al., 2001) (Y. Wang and E.A.E., unpublished data) and promotes membrane recruitment of Ste5p; (Mahanty et al., 1999) (Y. Wang and E.A.E., unpublished data).
Currently it is not known how Ste5p is affected by nuclear shuttling. This process could co-localize Ste5p with nuclear modifying enzymes or alter its conformation through interactions with shuttling factors or other proteins that are concentrated in the nucleus. The major NLS of Ste5p overlaps with sequences involved in interactions between its N- and C-termini (Mahanty et al., 1999; Sette et al., 2000), and putative NES sequences lie near the leucine-zipper oligomerization domain (Y. Wang and E.A.E., unpublished data). This suggests that nuclear shuttling and oligomerization are coordinated, an idea that is supported by a variety of evidence (Y. Wang and E.A.E., unpublished data). Nuclear shuttling could co-localize Ste5p with other proteins involved in signaling; for example, with Fus3p (the MAPK) and Ste7p (the MAPKK), which are both nuclear and cytoplasmic (Choi et al., 1999) (Mahanty and E.A.E., unpublished data). Ste11p (the MAPKKK), however, is cytoplasmic (Posas et al., 1998) and does not concentrate in the nucleus (Mahanty et al., 1999). This raises the possibility that nuclear shuttling concentrates Ste5p with at least two kinases in the pathway and possibly guides them to the plasma membrane. Interestingly, the Fus3p-binding site in Ste5p lies next to the RING-H2 domain; phosphorylation of Ste5p therefore has the potential to alter the nature of this domain (Elion, 1995). As I will discuss below, it is also possible that nuclear shuttling links Ste5p to morphogenesis proteins required for polarized growth and recruitment to the plasma membrane.
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Interactions between Ste5p and regulators of polarized morphogenesis |
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During vegetative growth, Far1p is thought to be predominantly nuclear, whereas Cdc24p shuttles continuously through the nucleus and cytoplasm, a pool of Cdc24p being sequestered in the nucleus through an interaction with Far1p (Toenjes et al., 1999; Nern and Arkowitz, 1999; Shimada et al., 2000). Both proteins are exported from the nucleus to Gß at the projection tip in the presence of pheromone. The nuclear pool of Far1p might thus control the access of Cdc24p to Gß
(Blondel et al., 1999; Toenjes et al., 1999; Nern and Arkowitz, 2000; Shimada et al., 2000). Such a model is attractive, but we currently do not fully understand how the cell-polarity proteins are able to localize to the site of polarized growth in the absence of Far1p (Elion, 2000).
A key aspect of chemotropism is likely to be the asymmetric accumulation of the receptor and G protein at the internal landmark of the emerging projection tip (Ayscough and Drubin 1998; Arkowitz, 1999). The site for growth in the presence of pheromone may initially be chosen stochastically, before being biased to the correct location through a process that might involve receptor recycling (Arkowitz, 1999; Nern and Arkowitz, 2000b). Reinforcement of this bias might occur, in part, through signal amplification, perhaps through joint recruitment of the Ste5pMAPK-cascade complex and the Far1p-morphogenesis machinery (Fig. 5). Although genetic evidence argues that Cdc24p (a GNEF), Cdc42p (a G protein), Ste20p (a MAPKKKK), Bem1p (an adapter protein) and Far1p (another adapter protein) promote polarized growth independently of the mating MAPK cascade (Schrick et al., 1997), it is also clear that the morphogenetic response requires sufficient signaling through the MAPK cascade. Dose-response analysis shows that projection formation requires the highest level of signaling through the MAPK cascade, much more than transcriptional activation (Moore, 1983; Farley et al., 1999). Furthermore, functional analysis demonstrates that Fus3p is specifically required to promote projection formation and that it promotes polarized growth independently of its ability to promote transcription (Farley et al., 1999). The recruitment of Ste5p, similar to the morphogenesis proteins, is asymmetric and enriched at growth sites and suggests that the localization machinery reinforces the bias leading towards localized activation of the MAPK cascade and might also localize Fus3p to relevant substrates (such as Far1p). Bem1p complexes contain both Ste5p and Far1p (Lyons et al., 1996), and Bem1p is required for efficient activation of Fus3p (Lyons et al., 1996). Furthermore, the recruitment of Ste5p to the projection tip requires both Cdc24p and Cdc42p (Pryciak and Huntress, 1998) and Cdc24p can still be recruited to the cortex in the absence of Far1p (Nern and Arkowitz, 2000a; Shimada et al., 2000). Thus, it is conceivable that the Ste5p and Far1p complexes physically and functionally interact in the nucleus as well as at the plasma membrane. Indeed, the links between Ste5p and Bem1p raise the intriguing possibility that Ste5p and Far1p could perform redundant functions with respect to localizing cell-polarity proteins to Gß (Fig. 5).
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Ste5p and pathway specificity |
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Currently, no evidence proves or disproves any of these possibilities. The notion that Ste5p selectively binds MAPK Fus3p in vivo is particularly attractive because of its simplicity. However, it is not yet clear why Fus3p and Kss1p are both able to interact with the same small domain of Ste5p (Choi et al., 1994) or how Kss1p is activated by mating pheromone (Gartner et al., 1992; Ma et al., 1995; Cherkasova and Elion, 2001). One possibility is that the MAPK Kss1p resides in stable complexes along with multiple nuclear transcription factors of the invasive growth pathway (Cook et al., 1996; Madhani et al., 1997; Bardwell et al., 1998) but can be activated by a pool of MAPKK Ste7p that has dissociated from the Ste5p complex at the plasma membrane (Fig. 1). This fits with the observation that mating pheromone activates genes in the invasive growth pathway and the sterile vegetative growth pathway (Lee and Elion, 1999; Roberts et al., 2000), but it does not explain the interaction between Kss1p and Ste5p.
Evidence indicates that the activation of Fus3p, and not Kss1p, determines whether cells mate (Elion et al., 1990; Elion et al., 1991; Madhani et al., 1997; Farley et al., 1999). This specificity may be determined in part at the level of phosphorylation of specific targets involved in transcription, G1 phase arrest, morphogenesis, partner selection and fusion (Elion et al., 1990; Elion et al., 1993; Tyers and Futcher, 1993; Peter et al., 1993; Farley et al., 1999). Fus3p is both nuclear and cytoplasmic (Choi et al., 1999) and concentrates at the base and tips of mating projections in live cells (A. Levchenko, personal communication; M. Qi, P. Maslo and E.A.E., unpublished), which is consistent with its multiple roles in mating. Thus, it is conceivable that Ste5p helps target Fus3p to substrates, given their overlapping localization patterns. However, Ste5p might instead provide pathway specificity simply by ensuring efficient activation of Fus3p, the activation of Kss1p not being a deciding factor in whether a cell mates. Time-course analysis shows that Fus3p is active only in the presence of mating pheromone and is rapidly dephosphorylated upon pheromone removal, which suggests that it is constitutively inactivated by phosphatases (Choi et al., 1999). This is consistent with the fact that at least three phosphatases are involved in inactivation of Fus3p (Doi et al., 1994; Zhan et al., 1999). Biochemical evidence suggests that Fus3p is not active as a monomer or dimer and only maintains high specific activity in the Ste5p complex (Choi et al., 1999). Thus, Ste5p may provide pathway specificity by ensuring that a pool of Fus3p is kept active.
Another way in which Ste5p might promote pathway specificity is to prevent the activation of kinases that participate in other pathways. For example, Ste5p might segregate or insulate the kinases so that they are not activated by stimuli other than mating pheromone. This possibility is supported by the observation that a hyperactive form of MAPKK Ste7p is better at suppressing a protein kinase C pathway mutant when Ste5p is not present (Yashar et al., 1995) and glycerol gradient analysis that shows that the presence of Ste5p sequesters the MAPKKK Ste11p and Ste7p, preventing them from forming alternative complexes (Choi et al., 1999). If Ste5p does segregate kinases, its removal from a cell should elevate signaling in the other pathways that use the segregated kinases (Fig. 1). The available evidence does not suggest that this is a major form of control, because ste5 null mutants do not have obviously enhanced signaling through these pathways, although a minor increase has been detected (Lee and Elion, 1999). However, it is conceivable that the effect is masked by simultaneous release of inactive Fus3p, which inhibits the other pathways. Another possibility is that Ste5p promotes localized activation of the associated kinases so that they are less available to function in other pathways. For example, feedback attenuation by Fus3p could prevent further activation of the upstream kinases and limit their activation to the MAPK molecules associated with Ste5p. This possibility is supported by evidence that Fus3p feedback phosphorylates Ste7p, Ste11p and Ste5p (Errede et al., 1993, Kranz et al., 1994; Choi et al., 1994), although the significance of the feedback phosphorylation has not been established.
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Conclusions and perspectives |
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We also do not know whether Ste5p forms a transient or stable anchoring platform for the kinases at the plasma membrane. A consideration of the available data leads to a plausible model for the formation of a stable lattice through intermolecular multimerization and suggests that there is a tight link between Ste5p oligomerization and recruitment. Ferrell and co-workers have suggested that the existence of a multi-tiered processive MAPK cascade allows ultrasensitivity or switch-like responses to stimulus (Huang and Ferrell, 1996; Ferrell and Machleder, 1998). Although the presence of a scaffold is counterintuitive for maintaining a switch-like response, co-localization of proteins might be sufficient to enhance a response, depending on the relative concentrations of the scaffold and kinases (Ferrell, 1998; Burack and Shaw, 2000; Levchenko et al., 2000). The links between Ste5p and Cdc24p, and Cdc42p and Bem1p, raise the interesting possibility that these proteins play direct roles in the recruitment of Ste5p to the plasma membrane. Further work is needed if we are to clarify the nature of the recruitment event and to clarify whether simple concentration of Ste5p with its associated enzymes at specific sites at the plasma membrane underlies how Ste5p activates a MAPK cascade and whether Ste5p simultaneously regulates a morphogenetic response to a gradient of stimulus.
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