Synthetic polyamines: new compounds specific to actin dynamics for mammalian cell and fission yeast

Abstract

Actin is a major actor in the determination of cell shape. On the one hand, site-directed assembly/disassembly cycles of actin filaments drive protrusive force leading to lamellipodia and filopodia dynamics. Force produced by actin similarly contributes in membrane scission in endocytosis or Golgi remodeling. On the other hand, cellular processes like adhesion, immune synapse, cortex dynamics or cytokinesis are achieved by combining acto-myosin contractility and actin assembly in a complex and not fully understood manner. New chemical compounds are therefore needed to disentangle acto-myosin and actin dynamics. We have found that synthetic, cell permeant, short polyamines are promising new actin regulators in this context. They generate growth and stabilization of lamellipodia within minutes by slowing down the actin assembly/disassembly cycle and facilitating nucleation. We now report that these polyamines also slow down cytokinetic ring closure in fission yeast. This shows that these synthetic compounds are active also in yeasts, and these experiments specifically highlight that actin depolymerization is involved in the ring closure. Thus, synthetic polyamines appear to be potentially powerful agents in a quantitative approach to the role of actin in complex processes in cell biology, developmental biology and potentially cancer research.

Arginine deprivation: a potential therapeutic for cancer cell metastasis? A review

“…Polyamine is required during cell migration for forming lamellipodia, stress fibers, and integrin subunit a1. It also increases the K+ channel mediated Ca 2+ influx and aids FAK in inducing paxillin phosphorylation [32,[39][40][41][42]. Targeted inhibition of ODC was correlated with abnormal morphology of actin-cytoskeleton of metastatic cells during migration.…”

Rac1 promotes kidney collecting duct integrity by limiting actomyosin activity

“…To become active, WAVE2 is phosphorylated at tyrosine 150 within the WAVE regulatory complex, which leads to release of its VCA domain, which in turn binds to and activates the Arp2/3 complex that nucleates and polymerizes actin at branching points ( Leng et al, 2005 ; Mendoza, 2013 ). To assess whether alterations in actin dynamics caused the functional impairment of the Rac1 −/− CD cells, we treated them with the synthetic polyamine C8N6-BPA, which reduces the turnover of actin and enhances nucleation of actin at the cell edge to generate lamellipodia ( Nedeva et al, 2013 ; Riveline et al, 2014 ). C8N6-BPA increased the number of cells with lamellipodia and spreading area in Rac1 /f/ , but not Rac1 −/− , CD cells, indicating a defect of actin nucleation and branching ( Fig.…”

Cholate-conjugated cationic polymers for regulation of actin dynamics

“…8,9 Also, many naturally occurring drugs like latrunculin A and B, cytochalasin D, jasplakinolide, and phalloidin, can bind to actin and alter actin filament dynamics. 10,11 A vast number of literature reports have shown that actin polymerization can be promoted in the presence of positively charged (surfaces) molecules like polyamines, 12 cationic liposomes, 13 positively charged lipids, 14 and peptides 15 via possible non-specific electrostatic binding. 16,17 However, the practical relevance of most of the synthetic substrates is limited due to their high measure of toxicity; thus, new designs and synthesis of actin-interacting materials with low toxicity are of tremendous bio-importance such as in nucleocytoplasmic transport, and wound healing.…”