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. 2002 Apr;7(2):200–206. doi: 10.1379/1466-1268(2002)007<0200:aotmap>2.0.co;2

壽Activation of the mitogen-activated protein kinase pathways by heat shock

Sonia Dorion 1, Jacques Landry 1,1
PMCID: PMC514818  PMID: 12380688

Abstract

In addition to inducing new transcriptional activities that lead within a few hours to the accumulation of heat shock proteins (Hsps), heat shock activates within minutes the major signaling transduction pathways involving mitogen-activated protein kinases, extracellular signal–regulated kinase, stress-activated protein kinase 1 (SAPK1)–c-Jun N-terminal kinase, and SAPK2-p38. These kinases are involved in both survival and death pathways in response to other stresses and may, therefore, contribute significantly to the heat shock response. In the case of p38, the activation leads to the phosphorylation and activation of one of the Hsps, Hsp27. Phosphorylation occurs very early during stress, is tightly regulated, and results from the triggering of a highly specific heat shock–sensing pathway.

INTRODUCTION

The response to heat shock provides probably the most spectacular example of the cellular capacity to react in an active manner to toxic stress. An exposure to mild heat shock induces the development of thermotolerance, a state of extreme resistance to severe heat shock (Gerner and Schneider 1975). Thermotolerance develops within a few hours after exposure to heat shock and lasts for 2–3 days. Its development is accompanied by the transcriptional activation and accumulation of a group of highly conserved proteins called heat shock proteins (Hsps) (Landry et al 1982; Li and Werb 1982; Subjeck et al 1982). Until recently, the protective role of Hsps was confined to their chaperone function, ie, their capacity to bind heat-denatured proteins and prevent their irreversible aggregation (Lindquist 1986). However, recent findings reveal that Hsps can regulate both the signaling and the execution of major cell death pathways (reviewed in Jaattela 1999; Beere and Green 2001). Consequently, Hsps play a primordial role in the resistance to a variety of toxic agents and situations that do not necessarily involve protein denaturation (Mehlen et al 1996; Mosser et al 1997; Beere et al 2000; Gabai et al 2000; Nylandsted et al 2000; Pandey et al 2000).

This evolutionary conserved response is triggered at least in part by heat-induced accumulation of denatured proteins (Ananthan et al 1986). At normal temperatures, Hsp70, Hsp40, and Hsp90 are expressed at low basal level and maintain the heat shock transcriptional factor (HSF) in a repressed state. Relief of repression occurs via the titration of the Hsps by the stress-induced unfolding and denaturation of native proteins (Lindquist and Craig 1988; Mosser et al 1990; Morimoto 1993; Zou et al 1998). This results in the activation of HSF, the activation of Hsp genes, and the accumulation of Hsps, which contributes in enhancing cell survival against subsequent protein-denaturing heat shock and in turning off HSF.

Hsp accumulation occurs in terms of hours. Another evolutionary conserved heat shock response develops in minutes and leads to the activation of the major signaling transduction pathways involving mitogen-activated protein (MAP) kinases, ERK, stress-activated protein kinase 1 (SAPK1)–c-Jun N-terminal kinase (JNK) (called here JNK), and SAPK2/p38 (called here p38) (Dubois and Bensaude 1993; Rouse et al 1994; Adler et al 1995; Guay et al 1997; Dorion et al 1999). These signaling cascades play a central role in the regulation and determination of cell fate, such as growth, differentiation, or apoptosis in numerous physiological as well as stress conditions. The mechanisms of activation and the roles of these pathways during heat shock have been the subject of recent investigations.

MECHANISMS OF ACTIVATION OF THE MAP KINASE PATHWAYS BY HEAT SHOCK

MAP kinases are activated in a cascade of phosphorylation reactions in which individual MAP kinases are phosphorylated and activated by a kinase of the MAP kinase kinase (MAPKK) family, which is itself phosphorylated and activated by an MAPKK kinase (MAPKKK). In general, each group of MAP kinases is activated by a rather specific MAPKK (or a restricted number of specific MAPKK), whereas several MAPKKK appear to exist in each pathway, each with specific mechanisms of activation. Upstream of the MAPKKK, the signaling molecules involve kinases, adaptors, and receptors or sensors, which connect the pathway to specific stimuli (Widmann et al 1999; Chang and Karin 2001). Data available on the heat-regulated activation of the MAP kinases suggest that 3 distinct mechanisms are involved for the activation of the 3 MAP kinases ERK, JNK, and p38 and that there exists a great deal of specificity in the activation of these pathways by heat shock relative to other stresses. The activation of the MAP kinase pathways by heat shock is illustrated in Figure 1.

Fig. 1.

Fig. 1.

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 Proposed mechanisms for the activation of the mitogen-activated protein kinase pathways by heat shock. Whereas the extracellular signal-regulated kinase pathway appears to be activated after the agonist-independent phosphorylation and activation of the epidermal growth factor receptor and the c-Jun N-terminal kinase (JNK) pathway, as a result of the inactivation of a protein phosphatase of JNK (PPase), the p38 pathway is activated downstream of a specific heat shock sensor or sensing pathway (indicated by the question mark). See text for details

Activation of ERK by heat shock involves the agonist-independent phosphorylation and activation of the epidermal growth factor (EGF) receptor, followed by the activation of the MAPKKK Raf1 (Lin et al 1997). This is reminiscent of other cellular stresses such as ultraviolet (UV) light and hyperosmolarity, both of which use growth factor receptors as stress sensors upstream of the MAP kinase pathways. Activation of the JNK signal transduction pathway by these agents results from perturbations of the cell membrane, which induce conformation changes in the receptors. These stresses induce activation, clustering, and internalization of the receptors for EGF, tumor necrosis factor α (TNFα), and interleukin (IL)-1 and the subsequent subversion of signaling pathways normally used upon agonist activation (Rosette and Karin 1996). However, several observations strongly suggest that heat shock activation of p38 and JNK does not proceed through these receptors: (1) activation of the p38 pathway by heat shock is not blocked by a selective EGF receptor inhibitor (tryphostin AG1478) or by a dominant negative mutant of the EGF receptor (Lin et al 1997); (2) there is no cross-desensitization of the p38 pathway between heat shock and EGF or other growth factors or cytokines (Dorion et al 1999); (3) suramin, an extracellular antagonist of several membrane receptors, has no effect on heat shock activation of p38, whereas it completely blocks activation of ERK by heat shock and of JNK by UV light and hyperosmotic shock (Sachsenmaier et al 1994; Rosette and Karin 1996; Lin et al 1997); and (4) heat shock activation of JNK does not require stimulation by upstream kinases (Meriin et al 1999). Indeed, although MKK4 (the common MAPKK of JNK) activity is essential for heat-induced JNK activation, as demonstrated using the expression of MKK4 dominant-negative mutant in various cell lines or by gene knockout in either mouse embryonic stem (ES) cells or fibroblasts (Zanke et al 1996; Nishina et al 1997; Ganiatsas et al 1998; Meriin et al 1998), a major mechanism for heat shock–induced activation of JNK appears instead to be the direct inhibition of a phosphatase that normally inactivates JNK (Meriin et al 1999). In the absence of the JNK phosphatase, the basal activity of MKK4 would be sufficient to activate JNK. This mechanism is specific for JNK. Heat shock activation of p38 does not proceed through inhibition of a phosphatase (Meriin et al 1999).

In contrast to heat shock activation of JNK, that of p38 requires the participation of specific upstream kinases, namely, the MAPKK MKK3/6 and the MAPKKK apoptosis signal-regulating kinase-1 (ASK1) (Dorion et al, in preparation). The role of ASK1 in the activation of p38 is not specific to heat shock but clearly does not mediate all stress-induced activation of p38. Overexpression of ASK1 (K709M), a catalytically inactive mutant of ASK1, inhibits heat shock- and H2O2-induced p38 activation but not the activation of p38 by hyperosmotic shock or arsenite (Dorion et al, in preparation). In the case of oxidative stress, it has been shown that ASK1 is the MAPKKK responsible for the activation of both the MKK3/6 (leading to activation of p38) and MKK4/7 (leading to activation of JNK) (Ichijo et al 1997). In this case, the redox regulatory protein thioredoxin (TRX) acts as the oxidative stress sensor (Saitoh et al 1998). Under normal conditions, reduced TRX binds to and inhibits ASK1. Upon oxidative stress, oxidation of TRX triggers its dissociation from ASK1, allowing the activation of ASK1 through autophosphorylation and oligomerization, leading to the subsequent activation of downstream kinases. ASK1 is also involved in the activation of p38 and JNK by TNFα (Hoeflich et al 1999). In that case also, reactive oxygen species produced in response to TNF cause the oxidation-mediated dissociation of TRX from ASK1, enabling the binding of TNF-associated factor 2 to ASK1 and its activation (Saitoh et al 1998; Hoeflich et al 1999; Liu et al 2000). Interestingly, heat shock activation of ASK1 does not proceed through a redox-dependent mechanism. p38 induction is not antagonized by antioxidant pretreatments (Huot et al 1995) and is not accompanied by the dissociation of TRX from ASK1 (Dorion et al, in preparation). Instead, heat shock activation of ASK1 appears to involve the release of another repressor of ASK1, glutathione S-transferase Mu1-1 (GSTM1-1).

GSTs are most commonly known as enzymes that conjugate reduced glutathione to a variety of substrates (Hayes and Pulford 1995). In addition to this catalytic activity, GSTs can also serve as nonenzymatic binding proteins (known as ligandins) interacting with various lipophilic compounds like steroid hormones (Hayes and Pulford 1995). Recently, Cho et al (2001) reported that GSTM1-1 interacts with ASK1 and, in a manner similar to TRX, acts as a natural inhibitor of ASK1. The inhibition occurs independently of GST enzymatic activity. Interestingly, overexpression of GSTM1-1 inhibits heat shock induction of the p38 pathway, and heat shock, but not H2O2, causes the dissociation of GSTM1-1 from ASK1 (Dorion et al, in preparation). The specific mechanisms responsible for the heat shock–induced dissociation of GSTM1-1 from ASK1 and the subsequent activation of ASK1 have not yet been identified. Because dissociation occurs independently of the well-known catalytic activity of GST in intracellular glutathione metabolism, it may involve the capacity of GSTM1-1 to bind nonenzymatically hydrophobic compounds. The heat shock–induced release of hydrophobic molecules such as sphingosine and ceramide (Chang et al 1995; Dickson et al 1997; Pena et al 1997; Chung et al 2000) may titrate GSTM1-1 out, thereby allowing activation of ASK1.

In mammalian cells the p38 pathway is activated by various stresses and numerous types of agonists, including tyrosine kinase, serpentine, or cytokine receptor activators (reviewed in Widmann et al 1999). Hence, multiple sensing pathways exist that must eventually converge on the main signaling elements of p38. For example, as seen earlier, ASK1 appears as the point of convergence of the heat shock–and oxidative stress–sensing pathways. The heat-sensing pathway appears highly specific, as suggested by classical homologous and heterologous desensitization experiments. Indeed, heat shock treatment induces a total desensitization to activation by heat shock of all elements of the heat shock–induced p38 pathways known until now, including MAPKAP kinase-2 and Hsp27 but also MKK3/6 and ASK1 (Landry et al 1991; Dorion et al 1999). This desensitization is strictly homologous. Heat shock–desensitized cells remain fully responsive to all other agonists tested, such as thrombin, TNF, EGF, platelet-derived growth factor, serum sphingomyelinase, tetradecanoylphorbol-13 acetate, and to stresses, such as hyperosmolarity, arsenite, and H2O2 (Dorion et al 1999). Such a specificity of desensitization implies the existence of a down-regulatable signaling element upstream of ASK1, which is specifically used by heat shock. The possibility that a general heat shock sensor (or sensing pathway) might exist in all mammalian cells and be responsible for activating heat-specific events leading to p38 activation is thus plausible. Interestingly, a transmembrane protein designated Wsc1-Hcs77 acts as a heat shock sensor and is essential for activation of the MAPK Mpk1 by heat shock in yeast (Delley and Hall 1999; Philip and Levin 2001). The protein is thought to function as a mechanosensor of cell wall stress and may detect changes in membrane fluidity induced by heat shock. Furthermore, a receptor for noxious heat has been described in afferent neurons that are activated by harmful stimuli and give rise to pain (Caterina et al 1997). The same receptor is activated by capsaicin, the active ingredient of “hot” chili pepper.

ROLE AND REGULATION OF MAP KINASE ACTIVATION BY HEAT SHOCK

In theory, such a rapid activation of the MAP kinases early during heat shock can either serve to trigger homeostatic responses or else be used to signal cell death. In fact both prosurvival and prodeath functions have been ascribed to MAP kinase activation, depending on the cellular context and the inducer. For example, ASK1 has been initially described in the context of apoptosis and participates in cell death processes inasmuch as cell death induced by various stresses (eg, TNF and oxidative stress) is remarkably reduced by disruption of the ASK1 gene in the mouse (Tobiume et al 2001). However, ASK1 has also been attributed a role in determining the distinct cell fate, such as survival, proliferation, and differentiation (review by Matsuzawa and Ichijo 2001). Overexpression of wild-type ASK1 or the constitutively active mutant can either induce apoptosis or differentiation (Ichijo et al 1997; Chang et al 1998; Chen et al 1999; Hatai et al 2000; Kanamoto et al 2000). The contrasting effects obtained likely depend of the cell type. However, qualitative aspects of the activation are also likely important. For instance, an early, transient activation of JNK or p38 (or both) is usually associated with survival or differentiation, whereas a late, sustained activation of these kinases generally correlates with apoptosis (Guo et al 1998; Roulston et al 1998).

In this context, it is not surprising that activation of the MAP kinases is tightly regulated during heat shock. As discussed earlier, heat shock induces a desensitization of the p38 pathway, and the desensitization kinetics corresponds exactly to the kinetics of thermotolerance development (Landry et al 1991; Dorion et al 1999). In fact, heat shock–induced desensitization of the p38 pathways correlates better than the concentration of Hsp27 or Hsp70 with heat-induced thermotolerance (Landry et al 1991). A similar desensitization of the JNK pathway has also been reported (Gabai et al 1997; Mosser et al 1997), meaning that neither kinase is activated in thermotolerant cells. This would suggest that activation of p38 and JNK early during heat shock is a mechanism of heat-induced cell death and that the desensitization process may be a mechanism of thermotolerance. Support for this idea has been obtained in the case of JNK, where blocking its activation was shown to be sufficient to protect cells against various stressors including heat shock (Gabai et al 2000; Mosser et al 2000; Park et al 2001). Recent studies further proposed that regulation of JNK activity is a mechanism of Hsp70-mediated protection. Overexpression of Hsp70 can inhibit JNK activation by various stimuli, including heat shock, sorbitol, TNF, UV light, IL-1, and H2O2 (Gabai et al 1997; Mosser et al 1997), through a mechanism involving the direct binding of Hsp70 to JNK (Park et al 2001) or an Hsp70-mediated protection of a JNK phosphatase from heat denaturation (Meriin et al 1999). The inhibition of JNK activity could therefore be a factor of acquired thermotolerance.

In contrast, the activation of the p38 pathway leads to the phosphorylation of one of the Hsps, Hsp27 (Chrétien and Landry 1988; Landry et al 1991; Huot et al 1995), an event that is generally assumed to be protective. Phosphorylation of Hsp27 is catalyzed by MAPKAP kinase-2, a serine-protein kinase itself activated by phosphorylation by p38 (Rouse et al 1994; Huot et al 1995). Upon phosphorylation, major changes are induced in the supramolecular organization of Hsp27, changes that are thought to activate a homeostatic function of the protein (Lambert et al 1999). One of the phosphorylation-modulated functions of Hsp27 is the regulation of actin dynamics. Hsp27 phosphorylation is involved in the stabilization of the actin filament during stress (particularly oxidative stress) and also in mediating rapid change in actin filament dynamics in response to stimuli that activate the p38 pathway (Lavoie et al 1995; Guay et al 1997; Landry and Huot 1999; Schafer et al 1999). Hsp27 phosphorylation occurs not only after heat shock but also after stimulation by various types of agonists, including tyrosine kinase, serpentine, or cytokine receptor activators (Arrigo and Landry 1994). Although it is essential in several physiological events requiring modulation of actin polymerization, this activity of Hsp27 can also mediate inappropriate actin polymerization activity and lead to extensive cell blebbing and apoptosis. This was shown to occur when an incorrect balance is generated between the activity of p38 and that of ERK, as for example, during treatment with toxic agents such as cisplatin (Huot et al 1998; Deschesnes et al 2001). Toxic effects resulting from excessive or badly timed actin polymerization activities may also occur upon stress, when the concentration of Hsp27 is very high (Deschesnes et al 2001). It is thus possible that p38 desensitization is protective during thermotolerance, preventing an overload in the homeostatic response and stringently circumscribing the induced stimulatory effects in a given time frame. This restriction in the duration of activation of the signaling pathway may be important to ensure that an adequate response is generated.

CONCLUDING REMARKS

Recent progress in the field of cellular stress has led to the emergence of the new concept that the cell response to stress is not just a passive consequence of induced damages to functions, structures, or molecules. The response to stress also results from the activation of specific stress-sensitive signaling pathways that trigger homeostatic responses of survival, repair, and adaptation. Even cell death can result from an active, energy-demanding, and signaled process, regulated by sophisticated mechanisms transducing the life-and-death decisions of stress sensors.

Mammalian cells respond to heat stress in a highly orchestrated manner under the control of 2 evolutionary conserved mechanisms: the activation of HSF leading to Hsp accumulation and the MAP kinases cascades. These 2 systems are finely regulated and interconnected: Hsp regulating MAP kinase activation and MAP kinases regulating Hsp activities and perhaps also their activation (Dai et al 2000). Much remains to be learned concerning the mechanism of activation and the role of the MAP kinase in the heat shock response. The existence of a specific heat-sensing pathway regulating their activation suggests important and heat-specific roles for this response.

Acknowledgments

This work was supported by the Canadian Institutes of Health Research, grant MT-7088. S.D. was supported by a studentship from the Medical Research Council of Canada.

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