Cofilin is a pH sensor for actin free barbed end formation: role of phosphoinositide binding.
Christian Frantz,Gabriela Barreiro,Laura Dominguez,Xiaoming Chen,Robert J. Eddy,John S. Condeelis,Mark J. S. Kelly,Matthew P. Jacobson,Diane L. Barber +8 more
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A molecular mechanism whereby cofilin acts as a pH sensor to mediate a pH-dependent actin filament dynamics is suggested, which suggests that it has a more complex behavior in cells.Abstract:
Newly generated actin free barbed ends at the front of motile cells provide sites for actin filament assembly driving membrane protrusion. Growth factors induce a rapid biphasic increase in actin free barbed ends, and we found both phases absent in fibroblasts lacking H+ efflux by the Na-H exchanger NHE1. The first phase is restored by expression of mutant cofilin-H133A but not unphosphorylated cofilin-S3A. Constant pH molecular dynamics simulations and nuclear magnetic resonance (NMR) reveal pH-sensitive structural changes in the cofilin C-terminal filamentous actin binding site dependent on His133. However, cofilin-H133A retains pH-sensitive changes in NMR spectra and severing activity in vitro, which suggests that it has a more complex behavior in cells. Cofilin activity is inhibited by phosphoinositide binding, and we found that phosphoinositide binding is pH-dependent for wild-type cofilin, with decreased binding at a higher pH. In contrast, phosphoinositide binding by cofilin-H133A is attenuated and pH insensitive. These data suggest a molecular mechanism whereby cofilin acts as a pH sensor to mediate a pH-dependent actin filament dynamics.read more
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Dysregulated pH: a perfect storm for cancer progression.
TL;DR: The central role of pH sensors in cancer cell adaptations is highlighted and how dysregulated pH could be exploited to develop cancer-specific therapeutics is suggested.
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Random versus directionally persistent cell migration.
TL;DR: Factors such as the topography of the extracellular matrix, the cellular polarity machinery, receptor signalling, integrin trafficking, Integrin co-receptors and actomyosin contraction converge on regulation of the Rho family of GTPases and the control of lamellipodial protrusions to promote directional migration.
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Amiloride inhibits macropinocytosis by lowering submembranous pH and preventing Rac1 and Cdc42 signaling
Mirkka Koivusalo,Christopher Welch,Hisayoshi Hayashi,Cameron C. Scott,Moshe Kim,R. Todd Alexander,Nicolas Touret,Klaus M. Hahn,Sergio Grinstein +8 more
TL;DR: Inhibitors of Na+/H+ exchange proteins block macropinocytosis by lowering the pH near the plasma membrane, which in turn inhibits actin remodeling by Rho family GTPases.
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ADF/Cofilin: A Functional Node in Cell Biology
TL;DR: It is argued that this ability to respond to physiological changes by modulating those same changes makes the ADF/cofilin protein family a homeostatic regulator or 'functional node' in cell biology.
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pH sensing and regulation in cancer.
TL;DR: Some of the major players in proton sensing at the plasma membrane and their downstream consequences in cancer cells are discussed and how these pH-mediated changes affect processes such as migration and metastasis are discussed.
References
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Thomas A. Halgren,Robert B. Murphy,Richard A. Friesner,Hege S. Beard,Leah L. Frye,W. Thomas Pollard,Jay L. Banks +6 more
TL;DR: Comparisons to results for the thymidine kinase and estrogen receptors published by Rognan and co-workers show that Glide 2.5 performs better than GOLD 1.1, FlexX 1.8, or DOCK 4.01.
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Cellular Motility Driven by Assembly and Disassembly of Actin Filaments
Thomas D. Pollard,Gary G. Borisy +1 more
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