Positive feedback between Cdc42 activity and H+ efflux by the Na-H exchanger NHE1 for polarity of migrating cells

Frantz, Christian; Karydis, Anastasios; Nalbant, Perihan; Hahn, Klaus M.; Barber, Diane L.

doi:10.1083/jcb.200704169

Cited by 118 publications

(115 citation statements)

References 45 publications

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“…Increased pH i is an evolutionarily conserved signal necessary for several stages of cell migration in addition to FA remodeling, including polarity (12,14,25) and the assembly of cytoskeletal filaments (14,31). Moreover, in addition to talin a number of proteins have pH-dependent actin binding, including HIP1 (17), cofilin (32), and villin (33).…”

Section: Discussionmentioning

confidence: 99%

“…Third is regulated talin affinity for F-actin, which our current data and previous findings (8)(9)(10) show is pH-dependent. Because integrin activation (11,29), growth factors (11,25,30), and monolayer wounding (25) stimulate NHE1 activity and increase pH i , pH-dependent FA remodeling could be regulated by different migratory cues. Our current study suggests that pH-regulated FA remodeling by dynamic changes in talin affinity for F-actin may be one of several complementary mechanisms controlling FA turnover.…”

Section: Discussionmentioning

confidence: 99%

“…5E). In E266I cells, the increase in migratory velocity with GFP-talin-H2418F was significant (P Ͻ 0.01, n ϭ 20) but smaller in magnitude compared with the decrease in WT cells, most likely because absence of NHE1 activity in motile cells also impairs polarity (25) and actin filament assembly (14). These data indicate that substitution of H2418F in talin changes FA stability, attenuating turnover in WT cells with pH i of 7.5 but increasing turnover in E266I cells with pH i of 7.0.…”

Section: Talin-h2418f Has Decreased Ph-sensitive Actin Binding and Momentioning

confidence: 99%

“…Materials and methods for cell culture (11,24,25) and pHi measurements (24) were as previously described. Transient expression of proteins was obtained by transfection with FuGENE 6 (Roche).…”

Section: Methodsmentioning

confidence: 99%

“…NHE1 plays a central role in regulating pH i by catalyzing an electroneutral exchange of extracellular Na ϩ for intracellular H ϩ . The pH i of migrating WT and E266I cells is Ϸ7.5 and Ϸ7.0, respectively (25), and migratory rate of E266I cells is Ϸ8-fold slower than WT cells (12). FA turnover in cells migrating at the edge of a wounded monolayer was determined by real-time imaging of GFP-paxillin, which localized to FAs ( Fig.…”

Section: H2418f Mutant Shows Different Spectral Perturbations In Respmentioning

confidence: 99%

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Structural model and functional significance of pH-dependent talin–actin binding for focal adhesion remodeling

Srivastava

Barreiro

Groscurth

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

123

133

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Actin filament binding by the focal adhesion (FA)-associated protein talin stabilizes cell-substrate adhesions and is thought to be rate-limiting in cell migration. Although F-actin binding by talin is known to be pH-sensitive in vitro, with lower affinity at higher pH, the functional significance of this pH dependence is unknown. Because increased intracellular pH (pHi) promotes cell migration and is a hallmark of metastatic carcinomas, we asked whether it increases FA remodeling through lower-affinity talin-actin binding. Talin contains several actin binding sites, but we found that only the COOH-terminal USH-I/LWEQ module showed pH-dependent actin binding, with lower affinity and decreased maximal binding at higher pH. Molecular dynamics simulations and NMR of this module revealed a structural mechanism for pH-dependent actin binding. A cluster of titratable amino acids with upshifted pKa values, including His-2418, was identified at one end of the five-helix bundle distal from the actin binding site. Protonation of His-2418 induces changes in the conformation and dynamics of the remote actin binding site. Structural analyses of a mutant talin-H2418F at pH 6.0 and 8.0 suggested changes different from the WT protein, and we confirmed that actin binding by talin-H2418F was relatively pH-insensitive. In motile fibroblasts, increasing pHi decreased FA lifetime and increased the migratory rate. However, expression of talin-H2418F increased lifetime 2-fold and decreased the migratory rate. These data identify a molecular mechanism for pH-sensitive actin binding by talin and suggest that FA turnover is pH-dependent and in part mediated by pH-dependent affinity of talin for binding actin. intracellular pH ͉ NHE1 ͉ migration F ocal adhesion (FA) remodeling is a rate-limiting determinant in haptokinetic migration of adherent cells. At the leading edge of migrating cells, FAs undergo rapid cycles of assembly and turnover, creating and disrupting, respectively, sites of traction necessary for forward movement of the cell body. Force generation for traction requires linkage among the extracellular matrix, integrin receptors, and actin filaments. Actin filaments do not directly bind to the cytoplasmic domain of integrins but bind to integrin-associated FA proteins such as talin and vinculin. Although several mechanisms contribute to FA remodeling in migrating cells (1), emerging evidence indicates that talin plays a central role in the dynamic linkage between integrins and actin filaments necessary for cell migration (2, 3). Talin functions in distinct albeit complementary mechanisms that promote FA turnover. First is cleavage of talin by the protease calpain, which also modulates adhesion complex composition and likely signaling functions of talin (4). Second is regulated talin binding to actin filaments, which is proposed to act as a clutch to control FA turnover and membrane protrusion dynamics (3, 5-7). How actin binding by talin is dynamically regulated during cell migration, however, remains undetermined.Previous stu...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Talin-h2418f Has Decreased Ph-sensitive Actin Binding and Momentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: H2418f Mutant Shows Different Spectral Perturbations In Respmentioning

confidence: 99%

See 3 more Smart Citations

Structural model and functional significance of pH-dependent talin–actin binding for focal adhesion remodeling

Srivastava

Barreiro

Groscurth

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

123

133

View full text Add to dashboard Cite

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Electrochemical regulation of cell polarity and the cytoskeleton

2012

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Cell polarity plays a key role in regulating cell-cell communication, tissue architecture, and development. Both internal and external cues participate in directing polarity and feedback onto each other for robust polarization. One poorly appreciated layer of polarity regulation comes from electrochemical signals spatially organized at the level of the cell or the tissue. These signals which include ion fluxes, membrane potential gradients, or even steady electric fields, emerge from the polarized activation of specific ion transporters, and may guide polarity in wound-healing, development or regeneration. How a given electrochemical cue may influence cytoskeletal elements and cell polarity remains unclear. Here, we review recent progress highlighting the role of electrochemical signals in cell and tissue spatial organization, and elucidating the mechanisms for how such signals may regulate cytoskeletal assembly for cell polarity. V C 2012 Wiley Periodicals, Inc.

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Roles of Ion Transport in Control of Cell Motility

Stock

Ludwig

Hanley

et al. 2013

Comprehensive Physiology

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Cell motility is an essential feature of life. It is essential for reproduction, propagation, embryonic development, and healing processes such as wound closure and a successful immune defense. If out of control, cell motility can become life-threatening as, for example, in metastasis or autoimmune diseases. Regardless of whether ciliary/flagellar or amoeboid movement, controlled motility always requires a concerted action of ion channels and transporters, cytoskeletal elements, and signaling cascades. Ion transport across the plasma membrane contributes to cell motility by affecting the membrane potential and voltage-sensitive ion channels, by inducing local volume changes with the help of aquaporins and by modulating cytosolic Ca(2+) and H(+) concentrations. Voltage-sensitive ion channels serve as voltage detectors in electric fields thus enabling galvanotaxis; local swelling facilitates the outgrowth of protrusions at the leading edge while local shrinkage accompanies the retraction of the cell rear; the cytosolic Ca(2+) concentration exerts its main effect on cytoskeletal dynamics via motor proteins such as myosin or dynein; and both, the intracellular and the extracellular H(+) concentration modulate cell migration and adhesion by tuning the activity of enzymes and signaling molecules in the cytosol as well as the activation state of adhesion molecules at the cell surface. In addition to the actual process of ion transport, both, channels and transporters contribute to cell migration by being part of focal adhesion complexes and/or physically interacting with components of the cytoskeleton. The present article provides an overview of how the numerous ion-transport mechanisms contribute to the various modes of cell motility.

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Positive feedback between Cdc42 activity and H+ efflux by the Na-H exchanger NHE1 for polarity of migrating cells

Cited by 118 publications

References 45 publications

Structural model and functional significance of pH-dependent talin–actin binding for focal adhesion remodeling

Structural model and functional significance of pH-dependent talin–actin binding for focal adhesion remodeling

Electrochemical regulation of cell polarity and the cytoskeleton

Roles of Ion Transport in Control of Cell Motility

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