Novel PKCα-mediated phosphorylation site(s) on cofilin and their potential role in terminating histamine release

Sakuma, Megumi; Shirai, Yasuhito; Yoshino, Koichi; Kuramasu, Maho; Nakamura, Tomofumi; Yanagita, Toshihiko; Mizuno, Kensaku; Hide, Izumi; Nakata, Yoshihiro; Saito, Naoaki

doi:10.1091/mbc.e12-01-0053

Cited by 22 publications

(18 citation statements)

References 46 publications

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“…Ligands (proteins and small molecules, e.g. [40–42]) or post-translational modifications [43,44] that modulate cofilin occupancy can either inhibit or promote severing, depending on the initial cofilin binding density. Ligands or modifications that dissociate cofilin from filaments through competition or changes in binding affinity will promote severing when initial cofilin occupancy is high (ν cof > 0.5) and inhibit severing when cofilin occupancy is low (ν cof <0.5).…”

Section: Resultsmentioning

confidence: 99%

Competitive displacement of cofilin can promote actin filament severing

Elam

Kang

Cruz

2013

Biochemical and Biophysical Research Communications

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Cofilin is an essential actin filament severing protein that functions in the dynamic remodeling of the actin cytoskeleton. Filament severing activity is most efficient at sub-stoichiometric cofilin binding densities (i.e. <1 cofilin per actin filament subunit), and peaks when the number density of boundaries (i.e. junctions) between bare and cofilin-decorated segments is maximal. A model in which local topological and mechanical discontinuities lead to preferential fragmentation at boundaries accounts for available experimental data, including direct visualization of cofilin and actin during real-time severing events. The boundary-severing model predicts that ligands (e.g. other actin-binding proteins) that compete with cofilin for actin filament binding and modulate cofilin occupancy on filaments will alter the bare-decorated segment boundary density, and thus, the filament severing activity of cofilin. Here, we directly test this model prediction by evaluating the effects of phalloidin and myosin, two ligands that compete with cofilin for filament binding, on the actin filament binding and severing activities of cofilin. Our experiments demonstrate that competitive displacement of cofilin lowers cofilin occupancy and promotes severing when initial cofilin occupancy is high (i.e. >50%). Even in the presence of competitive ligands, maximum severing activity occurs when cofilin-decorated boundary density is highest, consistent with preferential fragmentation at boundaries. We propose a general “severodyne” framework for the modulation of cofilin-mediated actin filament severing by small molecule or actin-binding protein ligands that compete with cofilin for actin filament binding.

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Section: Resultsmentioning

confidence: 99%

Competitive displacement of cofilin can promote actin filament severing

Elam

Kang

Cruz

2013

Biochemical and Biophysical Research Communications

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“…Inactivation of cofilin is mainly ensured by phosphorylation through ROCK‐dependent LIM‐domain kinase (LIMK) and protein kinase α (PKCα) . Phosphorylated cofilin is unable to interact with F‐actin, and cell motility is consequently inhibited.…”

Section: Discussionmentioning

confidence: 99%

Increase in motility and invasiveness of MCF7 cancer cells induced by nicotine is abolished by melatonin through inhibition of ERK phosphorylation

Proietti

Catizone

Masiello

et al. 2018

Journal of Pineal Research

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Through activation of the ERK pathway, nicotine, in both normal MCF-10A and low-malignant breast cancer cells (MCF7), promotes increased motility and invasiveness. Melatonin antagonizes both these effects by inhibiting almost completely ERK phosphorylation. As melatonin has no effect on nonstimulated cells, it is likely that melatonin can counteract ERK activation only downstream of nicotine-induced activation. This finding suggests that melatonin hampers ERK phosphorylation presumably by targeting a still unknown intermediate factor that connects nicotine stimulation to ERK phosphorylation. Furthermore, downstream of ERK activation, melatonin significantly reduces fascin and calpain activation while restoring normal vinculin levels. Melatonin also counteracts nicotine effects by reshaping the overall cytoskeleton architecture and abolishing invasive membrane protrusion. In addition, melatonin decreases nicotine-dependent ROCK1/ROCK2 activation, thus further inhibiting cell contractility and motility. Melatonin actions are most likely attributable to ERK inhibition, although melatonin could display other ERK-independent effects, namely through a direct modulation of additional molecular and structural factors, including coronin, cofilin, and cytoskeleton components.

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“…Phosphorylation of other cofilin residues also regulates its activity. For example, protein kinase Cα (PKCα)-dependent phosphorylation at Ser23 and Ser24 terminates histamine degranulation 52 , and phosphorylation at Tyr68 by constitutively active SRC can promote the ubiquitin-mediated degradation of cofilin 53 .…”

Section: The Localization Of Cofilinmentioning

confidence: 99%

Functions of cofilin in cell locomotion and invasion

Bravo‐Cordero

Magalhaes

Eddy

et al. 2013

Nat Rev Mol Cell Biol

414

396

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Recently, a consensus has emerged that cofilin severing activity can generate free actin filament ends that are accessible for F-actin polymerization and depolymerization without changing the rate of G-actin association and dissociation at either filament end. The structural basis of actin filament severing by cofilin is now better understood. These results have been integrated with recently discovered mechanisms for cofilin activation in migrating cells, which led to new models for cofilin function that provide insights into how cofilin regulation determines the temporal and spatial control of cell behaviour.

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Novel PKCα-mediated phosphorylation site(s) on cofilin and their potential role in terminating histamine release

Cited by 22 publications

References 46 publications

Competitive displacement of cofilin can promote actin filament severing

Competitive displacement of cofilin can promote actin filament severing

Increase in motility and invasiveness of MCF7 cancer cells induced by nicotine is abolished by melatonin through inhibition of ERK phosphorylation

Functions of cofilin in cell locomotion and invasion

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