New anti-actin drugs in the study of the organization and function of the actin cytoskeleton

Spector, Ilan; Braet, Filip; Shochet, Nava R.; Bubb, Michael R.

doi:10.1002/(sici)1097-0029(19991001)47:1<18::aid-jemt3>3.0.co;2-e

Cited by 309 publications

(261 citation statements)

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“…Actin immunofluorescence and phalloidin staining demonstrated that expression of LIMK1-KD or cofilin S3A, like cytochalasin D, disrupted the delicate organization of actin filaments in the perinuclear region resulting in the accumulation of small actin aggregates; jasplakinolide, instead, induced the formation of large perinuclear actin aggregates, as previously described (Spector et al, 1999) (Figure 6 A and B, top; and Supplemental Figure 4C). Importantly, cytochalasin D (Figure 6A) but not jasplakinolide ( Figure 6B) strongly inhibited the exit of p75-GFP from the TGN, confirming our previous report that latrunculin B delays the TGN exit of p75-GFP during the first 30 min after release of the 20°C transport block (Musch et al, 2001).…”

Section: Tgn-trafficking Effects Of Limk1-kd and Cofilin S3a On P75-gmentioning

confidence: 99%

LIM Kinase 1 and Cofilin Regulate Actin Filament Population Required for Dynamin-dependent Apical Carrier Fission from theTrans-Golgi Network

Salvarezza

Deborde

Schreiner

et al. 2009

MBoC

108

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The functions of the actin cytoskeleton in post-Golgi trafficking are still poorly understood. Here, we report the role of LIM Kinase 1 (LIMK1) and its substrate cofilin in the trafficking of apical and basolateral proteins in Madin-Darby canine kidney cells. Our data indicate that LIMK1 and cofilin organize a specialized population of actin filaments at the Golgi complex that is selectively required for the emergence of an apical cargo route to the plasma membrane (PM). Quantitative pulse-chase live imaging experiments showed that overexpression of kinase-dead LIMK1 (LIMK1-KD), or of LIMK1 small interfering RNA, or of an activated cofilin mutant (cofilin S3A), selectively slowed down the exit from the trans-Golgi network (TGN) of the apical PM marker p75-green fluorescent protein (GFP) but did not interfere with the apical PM marker glycosyl phosphatidylinositol-YFP or the basolateral PM marker neural cell adhesion molecule-GFP. Highresolution live imaging experiments of carrier formation and release by the TGN and analysis of peri-Golgi actin dynamics using photoactivatable GFP suggest a scenario in which TGN-localized LIMK1-cofilin regulate a population of actin filaments required for dynamin-syndapin-cortactin-dependent generation and/or fission of precursors to p75 transporters. INTRODUCTIONThe organization of polarized intracellular trafficking to the plasma membrane (PM) involves a close cooperation between cargo proteins, adaptors and cytoskeletal elements that takes place at major sorting organelles, e.g., the Golgi complex and recycling endosomes (Bonifacino and Traub, 2003;Rodriguez-Boulan et al., 2005). Newly synthesized proteins destined for endosomes, lysosomes, and the basolateral PM of epithelial cells segregate into nascent post-Golgi or postendosomal vesicles via tyrosine, dileucine, or monoleucine sorting signals, clathrin adaptors, and accessory proteins (Bonifacino and Traub, 2003;Rodriguez-Boulan et al., 2005;Deborde et al., 2008).By contrast, proteins destined for the apical PM are sorted into nascent post-Golgi transporters via N-and O-glycans, specialized transmembrane or cytoplasmic domains or glycosyl phosphatidylinositol (GPI)-anchors that interact with lipid domains (rafts), lectins, or microtubule (MT) motors (Scheiffele et al., 1995;Simons and Ikonen, 1997;Yeaman et al., 1997;Delacour et al., 2005Delacour et al., , 2006Rodriguez-Boulan et al., 2005). It is very well established that MT motors of the kinesin or dynein families play key roles in the generation and transcytoplasmic transport of tubular and vesicular transporters destined to the apical PM of Madin-Darby canine kidney (MDCK) cells (Kreitzer et al., 2000;Noda et al., 2001;Tai et al., 2001;Allan et al., 2002;Musch, 2004;Jaulin et al., 2007). By contrast, our knowledge of the specific roles of the actin cytoskeleton in intracellular transport routes remains fragmentary, unlike the situation at the PM, where various mechanisms involving the actin cytoskeleton in endocytic routes have been well documented (Erickson et al., 1...

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Section: Tgn-trafficking Effects Of Limk1-kd and Cofilin S3a On P75-gmentioning

confidence: 99%

LIM Kinase 1 and Cofilin Regulate Actin Filament Population Required for Dynamin-dependent Apical Carrier Fission from theTrans-Golgi Network

Salvarezza

Deborde

Schreiner

et al. 2009

MBoC

108

View full text Add to dashboard Cite

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“…To analyze the effect of ␣-synucleins on the assembly of new actin filaments in living cells, N2A stable clones expressing ␣-synucleins were exposed for 5 min to LatA, a drug that induces depolymerization of actin filaments by sequestering actin monomers (Spector et al, 1999). After treatment, the drug was washed out and the cells were reincubated in conventional medium to let their cytoskeleton repolymerize.…”

Section: A30p ␣-Synuclein Induces the Formation Of Actinenriched Focimentioning

confidence: 99%

α-Synuclein and Its A30P Mutant Affect Actin Cytoskeletal Structure and Dynamics

Sousa

Bellani

Giannandrea

et al. 2009

MBoC

107

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The function of ␣-synuclein, a soluble protein abundant in the brain and concentrated at presynaptic terminals, is still undefined. Yet, ␣-synuclein overexpression and the expression of its A30P mutant are associated with familial Parkinson's disease. Working in cell-free conditions, in two cell lines as well as in primary neurons we demonstrate that ␣-synuclein and its A30P mutant have different effects on actin polymerization. Wild-type ␣-synuclein binds actin, slows down its polymerization and accelerates its depolymerization, probably by monomer sequestration; A30P mutant ␣-synuclein increases the rate of actin polymerization and disrupts the cytoskeleton during reassembly of actin filaments. Consequently, in cells expressing mutant ␣-synuclein, cytoskeleton-dependent processes, such as cell migration, are inhibited, while exo-and endocytic traffic is altered. In hippocampal neurons from mice carrying a deletion of the ␣-synuclein gene, electroporation of wild-type ␣-synuclein increases actin instability during remodeling, with growth of lamellipodia-like structures and apparent cell enlargement, whereas A30P ␣-synuclein induces discrete actin-rich foci during cytoskeleton reassembly. In conclusion, ␣-synuclein appears to play a major role in actin cytoskeletal dynamics and various aspects of microfilament function. Actin cytoskeletal disruption induced by the A30P mutant might alter various cellular processes and thereby play a role in the pathogenesis of neurodegeneration.

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“…6) is a diarrheic shellfish toxin produced by the dinoflagellate Dinophysis fortii and is also cytotoxic with IC 50 values ranging from 7.8 to 800 nM (Jung et al 1995). It inhibits actin polymerization (Hori et al 1999;Spector et al 1999). Pectenotoxin-2 binds to the cleft between subdomains Kobayashi et al (1997); g Matsunaga et al (1989); h Kobayashi et al (1993); i Roesener and Scheuer (1986); j Saito et al (1996); k Ojika et al (2007); l Bubb et al (1995); m Doi et al (1991); n Kobayashi et al (1989); o Terry et al (1997); p Saito et al (1998); q Sakai et al (1986) I and III of the "closed" conformation of actin monomer.…”

Section: Pectenotoxinsmentioning

confidence: 53%

“…Therefore, small molecules whose modes of action on actin are different from cytochalasins were required. During the last 20 years a large number of highly cytotoxic compounds were isolated from marine organisms (König et al 2006;Nagle et al 2006), and quite a few of these have been shown to affect actin filaments (Spector et al 1999;Fenteany and Zhu 2003). Interestingly, the majority of them mimic endogenous actin-binding proteins (McGough et al 2003;Silacci et al 2004).…”

Section: Actinmentioning

confidence: 99%

“…Natural product inhibitors of actin cytoskeleton dynamics are not only recognized as valuable molecular probes for dissecting complex mechanisms of cellular function, but also their potential use as chemotherapeutics has become a focus of scientific investigation. Cytoskeletal inhibitors are lethal to tumor cells and several of them have been included in the National Cancer Institute's Molecular Targets Development Program (Fenteany and Zhu 2003;Spector et al 1999). So far, however, no actin-binding drugs have entered clinical trials due to their lack of selectivity for diseased cells.…”

Section: Actin-targeted Marine Toxins In Basic and Preclinical Studiesmentioning

confidence: 99%

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Developmental Biology of Neoplastic Growth

Macieira‐Coelho¹

2005

Progress in Molecular and Subcellular Biology

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New anti-actin drugs in the study of the organization and function of the actin cytoskeleton

Cited by 309 publications

References 100 publications

LIM Kinase 1 and Cofilin Regulate Actin Filament Population Required for Dynamin-dependent Apical Carrier Fission from theTrans-Golgi Network

LIM Kinase 1 and Cofilin Regulate Actin Filament Population Required for Dynamin-dependent Apical Carrier Fission from theTrans-Golgi Network

α-Synuclein and Its A30P Mutant Affect Actin Cytoskeletal Structure and Dynamics

Developmental Biology of Neoplastic Growth

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