Department of Stomatology, University of California, San Francisco, California 94143
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ABSTRACT |
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hydrogen ion efflux; intracellular pH; molecular scaffold
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OVERVIEW OF NHE1 STRUCTURE AND INTERACTING SIGNALING MOLECULES |
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NHE1 AS SPATIALLY RESTRICTED SCAFFOLDING PLATFORM |
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What is the functional significance of restricting NHE1 to specialized membrane domains? The probable answer relates to the coordinate functions of NHE1 in ion transport, actin anchoring, and scaffolding. As an ion transport protein, localized H+ efflux by NHE1 likely promotes signaling or regulatory events. An increase in intracellular pH (pHi) has long been speculated to be necessary for de novo assembly of cytoskeletal filaments, as determined in earlier work on the fertilization of sea urchin eggs (3), the acrosomal reaction in ecinoderm sperm cells (58), and the motility of Ascaris sperm cells (23). At the leading edge of migrating mammalian fibroblasts (14) and chemotaxing Dictyostelium cells (H. Patel and D. L. Barber, unpublished observations) NHE1 is necessary for maintaining polarity and directed movement by promoting local assembly and remodeling of the actin cytoskeleton. Localized H+ efflux at intercalated disks and transverse tubules in cardiac myocytes promotes gap junction conductance (69) and Ca2+ release pathways (70, 71) in regulating impulse conduction and excitation-contraction coupling. Some actions of NHE1, including increased cell proliferation, require global, but not localized, increases in pHi. The proliferative rate of fibroblasts expressing a mutant NHE1-KR/A that lacks ERM binding and is not localized in lamellipodia is similar to that of fibroblasts expressing wild-type NHE1 but approximately fourfold faster than fibroblasts expressing NHE1-E266I, which lacks ion translocation (16, 48). Mice with homologous inactivation of nhe1, however, are viable and lack morphogenic defects (4, 12), suggesting that in the absence of NHE1 compensatory or redundant pHi-regulatory mechanisms occur during development. Recent findings (72) indicate that in mice null for NHE1 the expression of other membrane transporters is altered, including an increase in the acid extruder NHE3 and a decrease in the acid loader AE3.
As an actin anchoring protein, NHE1 localized in specialized membrane domains acts to tether actin filaments to the plasma membrane and maintain cell shape (16). Actin anchoring and H+ efflux by NHE1 coordinately function in remodeling of the actin cytoskeleton and cell-substrate adhesions (14, 16). As a scaffolding protein, NHE1 clustered in distinct membrane domains likely facilitates a focal recruitment site for NHE1-interacting proteins, analogous to ionotrophic neurotransmitter receptors at postsynaptic sites (52) and T cell receptors at the immunologic synapse (68), which facilitate localized signal relay through forced proximity. Scaffolding by NHE1 could promote the localized assembly of signaling complexes and, coordinately with H+ efflux, facilitate signal relay.
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SCAFFOLDING BY NHE1 IN ASSEMBLY OF SIGNALING COMPLEXES |
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Phosphorylation of Ser703 on NHE1 by p90RSK induces activation of NHE1 by growth factors (55), and phospho-Ser703 binds 14-3-3 with high affinity (28). The 14-3-3 proteins have multiple functions, including shielding phosphorylated residues from dephosphorylation (2), and binding of 14-3-3
to a phosphorylated glutathione S-transferase fusion protein of the COOH terminus of NHE1 attenuates dephosphorylation by protein phosphatase 1 (28); 14-3-3 also binds to p90RSK and inhibits p90RSK catalytic activity (9). Hence, 14-3-3 binding to NHE1 likely sustains NHE1 activity by acting in a positive feedback loop that includes maintaining phosphorylation of Ser703 and competing for binding to p90RSK, which would increase p90RSK activity. Additionally, 14-3-3 proteins act as adaptors to sequester signaling complexes at the plasma membrane (2), and they may facilitate signal relay at an NHE1 scaffold by promoting the assembly of multiprotein complexes.
Several Ca2+-binding proteins bind directly to the COOH terminus of NHE1 to regulate ion exchange activity. The binding site for the EF-hand Ca2+-binding protein CHP1 was initially reported to include amino acids 520535 (33) but subsequently confirmed to require amino acids 567637 (42). Homologous proteins CHP2 (43) and tescalin (32, 36) also bind directly to NHE1, although binding sites have not been identified. Transient overexpression of CHP1 (33) and tescalin (32) attenuates NHE1 activity; however, an inhibitory action of CHP on NHE1 may reflect an artifact of overexpression because recent findings indicate that CHP may be an essential cofactor for promoting NHE1 activity. Preventing the binding of endogenous CHP to NHE1 by expressing a mutant NHE1 containing glutamine substitutions (526531Q) or by injecting a competing peptide of the CHP-binding domain of NHE1 decreases NHE1 activity (42). CaM binds to NHE1 at two sites, a high-affinity site (20 nM) at amino acids 637656 and a low-affinity site (
350 nM) at amino acids 657700 (62). Both CaM-binding sites reside within an autoinhibitory domain that suppresses NHE1 activity in quiescent cells by reducing the affinity for intracellular H+ sensing (63). Ca2+-dependent CaM binding is predicted to increase NHE1 activity by inducing a conformational change that relieves suppression by the autoinhibitory domain. CHP, like calcineurin B, can bind CaM, which suggests the possibility of cooperative or facilitated binding of CaM to NHE1. CHP, but not CaM, is an essential cofactor for maintaining NHE1 activity (42), and CHP binding to NHE1 could facilitate binding of CaM, particularly at the low-affinity CaM-binding site. CaM, like PIP2 and 14-3-3 proteins, facilitates the assembly of multiprotein complexes, thereby possibly enhancing a scaffolding function of NHE1.
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SCAFFOLDING BY NHE1 AND SIGNAL RELAY |
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If an NHE1 scaffolding platform facilitates signal relay, does NHE1 activity augment the output signal of assembled protein complexes? For a scaffold to increase signal output, computational modeling indicates that the abundance of the scaffold protein should not exceed that of the assembled signaling proteins, so as to prevent combinatorial inhibition (7, 29), analogous to the optimal balance of antigen and antibody in the precipitin reaction. This criterion is met by the lower abundance of NHE1 relative to a number of its associated proteins, including ERM proteins, CaM, and CHP. If NHE1 does increase the output signal of assembled protein complexes, an intriguing possibility is that localized H+ efflux alters protein affinities and catalytic activities to promote stronger or faster signals, or to regulate responses between switchlike or graded and processive. The binding affinities and activities of a number of proteins acting in signaling pathways regulated by NHE1 are pH sensitive, including cofilin (5, 47), gelsolin (27), and talin (18). The pH sensitivity of proteins is mediated by protonation of histidine residues. With an acidic dissociation constant (pKa) of 67, histidine is the only amino acid that undergoes strongly altered protonation within the physiological pH range of the cytosol. Site-directed substitution of histidine residues abolishes the pH sensitivity of a number of proteins, including the anion exchanger (24), the elongation factor Tu (13), the inwardly rectifying K+ channel GIRK4 (37), and an H+-sensing G protein-coupled receptor (35). More than 50% of enzymes have histidine residues in their active sites, including NIK, which has five histidines clustered at the ATP-binding pocket (142HLHIHHVIHRD152). Hence, H+ efflux by NHE1 might promote signal output by facilitating the catalytic activity of its associated kinases. This possibility can now be tested by using a mutant mammalian NHE1 that lacks H+ efflux but retains ERM binding, cytoskeletal anchoring, and localization in lamellipodia (14, 16).
The action of NHE1 as a membrane scaffold is a relatively new perspective that warrants further investigation. Current evidence favors a cooperative action of NHE1 as an ion transport protein and as a membrane scaffold in promoting the assembly of signaling complexes and signal relay in specialized membrane domains. As we learn more about the complexity of signaling units assembled at NHE1 and the role of NHE1 activity in signal output, we will better understand the pivotal role NHE1 plays in diverse cellular processes.
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GRANTS |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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