Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University and the Portland Veterans Affairs Medical Center, Portland, Oregon
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ABSTRACT |
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hypotonicity; transient receptor potential; hypertonicity; ion transport; tyrosine kinase
Although a variety of other cytoplasmic kinases have been implicated in osmotic signal transduction, including protein kinase C (151), myosin light chain kinase (21), and SGK1 (108), the discovery of the parallel mitogen-activated protein kinase (MAPK) modules, and the elucidation of their enormous importance in the cell response to anisotonicity (reviewed in Refs. 15 and 70), has dominated the literature on cell volume regulation. With this review, I call attention to a second essential group of cytoplasmic kinases, the SRC family kinases, with rapidly emerging importance in this field.
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RECEPTOR TYROSINE KINASES IN ANISOTONICITY |
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SRC FAMILY KINASES AND ANISOTONICITY |
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SFKs exhibit a modular architecture dominated by so-called "SRC homology," or SH domains (Fig. 1). SH1, the catalytic domain, is the site of tyrosine kinase activity. In the inactive state, a key tyrosine in this domain (Y416) blocks the substrate binding site; when autophosphorylated, this residue is displaced and substrate access is unimpeded. SH2 and SH3 are protein-protein interaction domains shared not only with other SFKs but also with many other signaling proteins. The SH2 domain binds phosphotyrosine motifs in either an inter- or intramolecular fashion. An intramolecular interaction of this type figures prominently in SFK regulation. Specifically, SFKs are maintained in an inactive conformation through constitutive phosphorylation of a COOH terminal tyrosine residue (Y527; Fig. 1). This COOH terminal phosphotyrosine binds the upstream SH2 domain, clamping the intervening catalytic SH1 domain in an inaccessible, and hence inactive, state. Unlike the regulatory tyrosine in the catalytic domain, this COOH terminal tyrosine is phosphorylated by another kinase, either COOH terminal SRC kinase (Csk) or Csk homologous kinase (Chk). Removal of the phosphate from this residue by any of several SFK-directed tyrosine phosphatases releases the SH2 domain, and exposes the catalytic domain (see Ref. 158 for review). Of note, the viral oncogene v-Src, lacking this COOH terminal inhibitory tyrosine, is constitutively activated; this mutant protein product entirely accounts for the transforming capacity of the Rous sarcoma virus (106). Interactions mediated via the SH3 domain, in contrast to the SH2 domain, are less dynamic; this motif binds proline-rich sequences harboring the -Pro-X-X-Pro- motif (where X represents any amino acid).
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Many, and perhaps all, SFKs are influenced by anisotonicity. Hypotonic stress activates LYN (67, 97, 156), LCK (77, 112), and SRC (147). Hypertonicity activates FYN (59, 112), HCK (68, 113), FGR (68), and YES (112) and exerts a variable effect upon SRC (59, 105). Therefore, although SFKs are activated by both hypo- and hypertonic stressors, the profile of individual SFKs activated may be unique to each stimulus. Alternatively, these apparent distinctions may be purely a consequence of the disparate models investigated, and specificity may reside upstream or downstream of SFK activation. There are few, if any, models where bidirectional cell volume regulation has been investigated vis-à-vis SFK activation.
Many osmotically responsive ion transport pathways can be influenced by SFKs, hence these kinases are well poised to regulate cell volume. In many instances, these pathways are influenced by anisotonicity and are influenced by activation or inactivation of SFKs; importantly, however, it has not been firmly established that SFKs mediate the effect of cell swelling or shrinkage on each channel or transporter, so much work remains to be done. The simplest way to conceptualize these events is to consider them in terms of the compensatory response to acute cell volume changes. Acute exposure to a hypertonic environment causes immediate water efflux and resultant cell shrinkage. The subsequent adaptive response is the rapid entry of ions to obligate restoration of cell volume. This process is called regulatory volume increase, or RVI. RVI occurs in response to hypertonic cell shrinkage. In contrast, when cells are acutely exposed to a hypotonic environment, they swell abruptly as water enters. To counteract this process and avert membrane rupture, the cells rapidly dump ions and osmotically active organic solutes thereby tempering the volume increase. This process is regulatory volume decrease, or RVD. The role of SFKs in transport of ions and osmotically active organic solutes (organic osmolytes) can be thought of in terms of these two opposing processes, activated independently to preserve cell volume. The molecular basis for both RVI and RVD has been extensively studied (see Refs. 71 and 151 for recent reviews); there are universals that apply to virtually all cells and tissues studied, and there are specifics that are highly model or cell-type dependent.
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ROLE FOR SFK IN RVD |
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Electroneutral K+-Cl symport activity is another well-conserved mechanism for effecting RVD (71). Of the four known isoforms (KCC14), KCC1, KCC3, and KCC4 are activated by hypotonicity (35, 50, 75, 90, 95, 111, 129), whereas KCC2 is insensitive to cell swelling (107). KCC1 is ubiquitously expressed and KCC2 is confined to the brain (see Ref. 151 for review). It has been suggested that KCC isoforms are activated through Ser/Thr-directed dephosphorylation (reviewed in Ref. 74), although a role for tyrosine phosphorylation has been incompletely explored. For example, in hippocampal neurons, KCC2 is activated by SRC and blocked by tyrosine kinase inhibitors (61). In erythrocytes, K+-Cl symport activity was substantially higher in cells isolated from mice null for the SFKs, FGR, and HCK (14).
Finally, RVD may be accomplished through the rapid efflux of organic solutes, such as amino acids, sugars, methylamines, and polyols. The volume-regulated anion channel contributes to this activity, hence one group's reference to it as the volume-sensitive organic osmolyte-anion channel (53). Undoubtedly, other pathways exist for osmolyte efflux and are also potentially influenced by SFKs. In erythrocytes of the spiny dogfish, for example, swelling-activated efflux of the organic osmolyte triethylamine was blocked by nonspecific inhibition of tyrosine kinases. The SFK LYN and the related cytoplasmic kinase SYK were implicated because increased activation of these kinases was observed in response to several stimuli known to cause cell swelling in this model (67), although evidence for direct involvement is needed.
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ROLE FOR SFK IN RVI |
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Among Cl/bicarbonate exchangers, AE-2 but not AE-1 is an effector of RVI (71). SFKs may play a role in agonist-inducible activation of AE-1 (110), although no data yet support a role in cell volume regulation.
Na+-K+-2Cl and Na+-Cl symport also contribute to RVI in a wide variety of tissues (71). Several Ser/Thr kinases including isoforms of PKC (44, 78) and MAPK (63, 78) have been implicated in regulation of NKCC1. However, the role of SFKs has been investigated in only one context. Erythrocyte NKCC, upon upregulation by the Ser/Thr phosphatase inhibitor calyculin, was modestly blocked by pharmacological inhibition of SFKs with PP1 (30).
Na+ channels and nonspecific cation channels may also be instrumental in RVI (71, 151). Activity of the epithelial sodium channel, ENaC, when heterologously expressed in NIH3T3 fibroblasts, can be inhibited by the peptide hormone endothelin-1. This effect is completely blocked by pretreatment with the SFK inhibitor PP2 (36). Nonselective cation channels in liver cells are activated by hypertonic stress. In this model system, intracellular dialysis with recombinant SRC leads to current activation even in the absence of osmotic stress (27). In further support of a potential role for SRC in RVI, cells genetically deficient in this kinase exhibit markedly increased susceptibility to apoptosis in response to transient hypertonic stress (86).
With respect to regulation of RVI effector pathways by SFKs, what is perhaps most striking is the relatively few model systems (and within each, the limited number of transport pathways) that have been investigated; clearly there are ample opportunities for investigation, especially in light of recent observations regarding the key role for SFKs in the regulation of gene transcription by hypertonic stress (see below).
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SPECIFICITY OF SFK FUNCTION IN THE CONTEXT OF RVI AND RVD |
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SFKs IN NONOSMOTIC ION TRANSPORT PATHWAYS |
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SFKs also regulate the ion fluxes that accompany neurotransmission, and these models have been scrutinized in extraordinary detail. Neurotransmitter receptors may be classified (19) as either ionotropic, with the receptor itself serving as the ion channel, or metabotropic, where a G protein coupled receptor indirectly activates ion flux via an intervening signal transduction pathway. The NMDA receptor, an example of the former, contributes to fast excitatory neurotransmission in the central nervous system. Simultaneous binding of both glycine and glutamate to the extracellular portion of the receptor opens a mono- and divalent cation channel. Activation of SFKs, and likely SRC itself, enhances NMDA receptor activity (120). The other principal glutamate receptor in CNS, the AMPA receptor, is also under the control of SFKs. This channel physically interacts with the SFK, LYN, in the cerebellum. Ligand engagement of the receptor activates LYN, which in turn participates in downstream signaling events (42). Therefore, ionotropic glutamate receptors may activate SFKs, as occurs with the NMDA receptor, or may in turn be activated by SFKs, as occurs with the AMPA receptor. The ion fluxes engendered by interaction of metabotropic neurotransmitters with their respective ligands are also heavily influenced by kinases of the SRC family (reviewed in Ref. 45).
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SFKs IN ANISOTONIC REGULATION OF CALCIUM HOMEOSTASIS |
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As alluded to above, mounting evidence points to a role for one or more members of the TRP family of calcium channels in cell volume regulation. In addition, new data underscore a role for SFKs in this process. The TRP channels comprise a family of six-transmembrane domain nonselective cation channels broadly divisible into three classes: 1) TRPC, or classic (short) TRP channels; 2) TRPM, or melastatin (long) TRP channels, so named for canonical member, melastatin; and 3) TRPV channels, named for the vanilloid-responsive founding member, TRPV1. Three additional classes of closely related channels include the mucolipins, polycystins, including polycystin-2, a molecular culprit in polycystic kidney disease, and the sensor of noxious cold, ANKTM1 (11). TRP channels of the TRPC family are widely expressed, and are generally activated by engagement of receptor tyrosine kinases and G protein coupled receptors in a phospholipase-dependent fashion; they are likely instrumental in store-operated calcium entry. TRPM channels serve diverse functions, befitting their large size; some, dubbed "chanzymes," even harbor catalytic kinase domains. Members of the TRPM family sense taste, anisotonicity, and noxious cold; others mediate calcium and magnesium uptake from the gut and kidney. TRPV channels are generally temperature responsive, although several members sense anisotonicity or serve to reabsorb calcium in the gut and kidney. In contrast to the ubiquitously expressed TRPC channels, expression of TRPV channels is primarily restricted to the nervous system and a few epithelia, such as the kidney and intestine (11).
With respect to TRP channel function and osmoregulation, data are emerging from diverse model systems. In yeast, a TRP channel homolog is activated by hypertonic stress (17). In Caenorhabditis elegans, the TRP channel OSM-9 is essential for appropriate avoidance of osmotic gradients (12); its genetic absence in worms can be complemented by its mammalian homolog, TRPV4 (81).
In mammalian systems, three TRP channels respond to anisotonicity in vitro: TRPM3, TRPV2, and TRPV4. TRPM3 is most abundantly expressed in kidney, although expression was also detected in central nervous system and testis (38, 76). Heterologous expression in human embyronic kidney-293 cells resulted in constitutive cation influx, and exposure of TRPM3-expressing cells to hypotonic medium (200 mosmol/kgH2O) was associated with an increase in intracellular calcium (38).
TRPV2 is primarily activated by heat and growth factors. Among other tissues, it is expressed in mouse aortic myocytes; these cells exhibit calcium entry in response to hypotonicity (96). Treatment of myocytes with antisense oligodeoxynucleotides against murine TRPV2 abrogated TRPV2 expression and the hypotonicity response. When heterologously expressed in Chinese hamster ovary cells, TRPV2 was activated by both membrane stretch and hypotonic cell swelling (96).
Comparatively little is known about signaling events leading to regulation of TRPM3 and TRPV2 by anisotonicity, whereas more details are available for TRPV4. Although TRPV4 was also identified in other contexts (16, 152), its significance in osmoregulation was solidified when it was cloned as the mammalian homolog of the C. elegans osmosensory protein, OSM-9 (79, 128). When heterologously expressed, TRPV4 is highly sensitive to a decrease in ambient tonicity (79, 128). This fact, coupled with the observation of some groups that TRPV4 is expressed in the blood-brain barrier-deficient brain nuclei responsible for sensing systemic tonicity (79, 80), suggested that TRPV4 might serve as the elusive sensor of plasma osmolarity. Whether TRPV4 functions as tonicity sensor or as an effector remains in dispute; knockout mice exhibit a relatively subtle phenotype with modestly elevated plasma [Na+] and an aberrant response to both salt and water stress (80, 93). A role for signaling by arachidonic acid metabolites in TRPV4 function has recently been proposed (150), perhaps consistent with earlier data broadly implicating this pathway in various models of RVD (see Ref. 151 for a review). PKC may also function in TRPV4 activation, although not in the context of hypotonic swelling (32).
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TRP CHANNELS ARE SUBJECT TO REGULATION BY SFKs |
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ANISOTONIC REGULATION OF NONTRANSPORT PROTEINS BY SFKs |
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MECHANOTRANSDUCTION: SFKs, INTEGRINS, AND OSMOTIC STRESS |
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Consistent with their role in mechanotransduction, integrins (and therefore SFKs) participate in osmotic signal transduction and cell volume regulation. Expression of 1-integrin is increased by hypertonic stress in a kidney epithelial cell model (124); this molecule also forms a complex with at least two other integral membrane proteins, CD-9 and HB-EGF (99, 125), that are themselves osmotically inducible (3, 66, 123). One of these components, HB-EGF, is subject to ectodomain cleavage and juxtacrine action in response to hypertonic stress as discussed above. A number of anisotonicity-induced transport processes including neurotransmitter release are blocked by a peptide inhibitor of integrin function (60, 85, 130). Hepatocyte cell volume is increased by hypotonicity and by insulin. In both cases, SFKs transmit the activating signal from integrins to downstream elements such as MAPKs (121, 147). Again underscoring the potential relationship between osmotic and mechanical stimuli, physical membrane traction on
1-integrins in ventricular myocytes activates a chloride current, which is blocked by pharmacological inhibition of SFKs (8). In addition, with respect to late events in cell volume regulation (see below), integrin clustering has been associated with increased transactivation by the tonicity-responsive transcription factor, TonEBP (56). SFKs also mediate shedding of the adhesion molecule, L-selectin, from hypertonically stressed neutrophils (113); this process requires upregulation of a "sheddase" activity analogous to the mechanism of EGF receptor transactivation by hypertonic stress. In aggregate, these data serve to underscore the close relationship between SFK activation and the functioning of integrins (and perhaps other adhesion molecules) in the cell response to anisotonicity.
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SFKs IN HYPERTONIC TRANSCRIPTIONAL REGULATION: TonEBP, p38, AND FYN |
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Much recent work has appropriately focused on the role of the tonicity-responsive MAPK, p38, in transcription mediated via TonE/TonEBP interaction; in most but not all cases, activation of p38 is required (69, 98, 122). An additional level of complexity, however, is emerging. Ferraris and coworkers (28) noted that the transactivating ability, or transcriptional competence, of a molecular chimera containing the TonEBP transactivation domain could be blocked with inhibitors of tyrosine kinase. Ko and coworkers (65) then established a potential molecular basis for this intriguing observation. Consistent with earlier findings, they noted that TonE-dependent transcription was partially blocked by pharmacological inhibition of p38 or by expression of dominant negative-acting p38 mutant. But they also observed that TonE-dependent transcription could be partially blocked with pharmacological inhibition of SFKs or via expression of dominant negative-acting mutant of the SFK, FYN (65). This group had previously shown that Fyn was activated by cell shrinkage (59). Moreover, in a FYN-deficient fibroblast cell line, inhibition of p38 alone almost completely blocked TonE-dependent transcription in response to hypertonic stress. FYN does not appear to influence TonEBP nuclear translocation (65), but other modalities of regulation have not been explored. These data, although acquired primarily through heterologous expression of an artificial reporter construct in an in vitro model, strongly support a role for SFKs in mediating tonicity-dependent transcription. Although direct evidence is lacking, these authors speculated that the FYN SH3 domain may interact with any number of canonical SH3 binding motifs in TonEBP.
In summary, SFKs integrate a large amount of upstream signaling information in the context of anisotonicity, including membrane tension and receptor activation, and transduce that information to a wide variety of cell volume regulatory effectors, including channels, transporters, and signaling proteins. In addition, SFKs are involved in the long-term adaptive response to anisotonicity by regulating transcription of tonicity-inducible genes. It is likely that SFKs participate in many more molecular aspects of cell volume regulation than has previously been recognized.
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GRANTS |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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