Filopodia and adhesion in cancer cell motility

Arjonen, Antti; Kaukonen, Riina; Ivaska, Johanna

doi:10.4161/cam.5.5.17723

Cited by 234 publications

(191 citation statements)

References 107 publications

Supporting

Mentioning

181

Contrasting

Order By: Relevance

“…This allosteric binding site has thus the potential to guide the design of novel class-specific myosin inhibitors. In particular, myosin VI and myosin X are interesting pharmaceutical targets due to their recently established role in cell migration and metastasis (21)(22)(23)(24).…”

Section: Discussionmentioning

confidence: 99%

Highly selective inhibition of myosin motors provides the basis of potential therapeutic application

Sirigu

Hartman

Planelles-Herrero

et al. 2016

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

View full text Add to dashboard Cite

Direct inhibition of smooth muscle myosin (SMM) is a potential means to treat hypercontractile smooth muscle diseases. The selective inhibitor CK-2018571 prevents strong binding to actin and promotes muscle relaxation in vitro and in vivo. The crystal structure of the SMM/drug complex reveals that CK-2018571 binds to a novel allosteric pocket that opens up during the "recovery stroke" transition necessary to reprime the motor. Trapped in an intermediate of this fast transition, SMM is inhibited with high selectivity compared with skeletal muscle myosin (IC 50 = 9 nM and 11,300 nM, respectively), although all of the binding site residues are identical in these motors. This structure provides a starting point from which to design highly specific myosin modulators to treat several human diseases. It further illustrates the potential of targeting transition intermediates of molecular machines to develop exquisitely selective pharmacological agents.M yosins comprise a family of ATP-dependent motor proteins capable of producing directed force via interaction with their track, the F-actin filament. Force production by these motors powers numerous cellular processes such as muscle contraction, intracellular transport, and cell migration and division (1). Several myosins have also been linked to genetic disorders where either gain or loss of motor function can lead to disease. These motor proteins represent promising targets for the development of drugs modulating force production in cells, tissues, and muscle (2-4). Here we report a selective, smallmolecule inhibitor of smooth muscle myosin (SMM) able to induce muscle relaxation. This mechanism of action has potential relevance for many diseases where smooth muscle contractility is central to the pathophysiology, such as asthma (5, 6) and chronic obstructive pulmonary disease (7).Smooth muscle contractility can be activated through different pathways. Existing airway smooth muscle relaxants, such as β-adrenergic agonists and muscarinic antagonists, ultimately inhibit the activity of SMM. However, they do so via specific upstream signaling pathways. Direct inhibition of SMM contractility has the advantage of relaxing contracted smooth muscle regardless of the molecular stimulus driving it. Moreover, application of SMM inhibitors to the airway provides a means of selectively modulating contractility of these tissues by delivering a high local concentration of drug. We thus set about identifying selective inhibitors of SMM that can effectively relax muscle in vivo, leading to the discovery of a highly selective, small-molecule inhibitor, CK-2018571 (CK-571).The detailed inhibitory mechanism of CK-571 was elucidated by a combination of in vitro characterization of the step in which the drug traps the motor and determination of the high-resolution structure of SMM cocrystallized with CK-571. The drug targets an intermediate state that occurs during the recovery stroke, the large conformational rearrangement that enables repriming of the motor. Blocking this critical transiti...

show abstract

Section: Discussionmentioning

confidence: 99%

Highly selective inhibition of myosin motors provides the basis of potential therapeutic application

Sirigu

Hartman

Planelles-Herrero

et al. 2016

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

View full text Add to dashboard Cite

show abstract

“…Previous studies showed that filopodia are sensors of chemotaxis. The filopodia projection detects changes in the environment and controls the direction of cell migration (Arjonen et al, 2011;Guiet et al, 2012). However, few studies have been published concerning the role of filopodia in OC differentiation and fusion.…”

Section: Introductionmentioning

confidence: 99%

New roles of filopodia and podosomes in the differentiation and fusion process of osteoclasts

et al. 2014

View full text Add to dashboard Cite

ABSTRACT. The cytoskeleton mediates various cellular processes such as differentiation and fusion, including in the filopodia and podosomes. However, apart from cell migration and formation of the sealing zone, little is known regarding the changes and related regulatory mechanisms of the cytoskeleton and additional roles of the filopodia and podosomes during the differentiation and fusion of osteoclasts. The cytomorphology and cytoskeleton of osteoclasts in the differentiation process were evaluated using tartrate-resistant acid phosphatase staining and immunofluorescence staining. Moreover, the expression levels of Rho GTPases and enzymes related to osteoclast differentiation and bone resorption were detected by quantitative reverse transcription-polymerase chain reaction. We detected 3 types of filopodia in osteoclast precursors and only 1 type of filopodia in undifferentiated cells. Mature osteoclasts were completely devoid of filopodia. Interestingly, cell fusion was highly specific, and the fusion New roles of filopodia and podosomes of osteoclasts initially occurred to the filopodia. Confocal images revealed that F-actin and microtubules significantly differed among fused cells. These results suggest that filopodia and podosomes not only play important roles in cell migration and the formation of sealing zones but also in the prefusion selectivity of 2 cells and the movement direction of the cell nucleus and cytoplasm during the fusion process. In addition, cdc42v1, RhoU, and RhoF regulate the formation of 3 types of filopodia during various stages of differentiation, while Rac1, Rac2, and filament A may be associated with cell selectivity during the fusion process.

show abstract

“…The classical view of filopodia is that they act as antennae to probe the extracellular environment for guidance cues, matrix composition and the presence of other cells (Mattila and Lappalainen, 2008;Mellor, 2010;Arjonen et al, 2011). It is therefore assumed that filopodia mediate endothelial tip cell migration to guide vascular sprout formation and vascular patterning.…”

Section: Introductionmentioning

confidence: 99%

Filopodia are dispensable for endothelial tip cell guidance

Phng¹,

Stanchi²,

Gerhardt

2013

Journal of Cell Science

View full text Add to dashboard Cite

SUMMARYActin filaments are instrumental in driving processes such as migration, cytokinesis and endocytosis and provide cells with mechanical support. During angiogenesis, actin-rich filopodia protrusions have been proposed to drive endothelial tip cell functions by translating guidance cues into directional migration and mediating new contacts during anastomosis. To investigate the structural organisation, dynamics and functional importance of F-actin in endothelial cells (ECs) during angiogenesis in vivo, we generated a transgenic zebrafish line expressing Lifeact-EGFP in ECs. Live imaging identifies dynamic and transient F-actin-based structures, such as filopodia, contractile ring and cell cortex, and more persistent F-actin-based structures, such as cell junctions. For functional analysis, we used low concentrations of Latrunculin B that preferentially inhibited F-actin polymerisation in filopodia. In the absence of filopodia, ECs continued to migrate, albeit at reduced velocity. Detailed morphological analysis reveals that ECs generate lamellipodia that are sufficient to drive EC migration when filopodia formation is inhibited. Vessel guidance continues unperturbed during intersegmental vessel development in the absence of filopodia. Additionally, hypersprouting induced by loss of Dll4 and attraction of aberrant vessels towards ectopic sources of Vegfa165 can occur in the absence of endothelial filopodia protrusion. These results reveal that the induction of tip cells and the integration of endothelial guidance cues do not require filopodia. Anastomosis, however, shows regional variations in filopodia requirement, suggesting that ECs might rely on different protrusive structures depending on the nature of the environment or of angiogenic cues.

show abstract

Filopodia and adhesion in cancer cell motility

Cited by 234 publications

References 107 publications

Highly selective inhibition of myosin motors provides the basis of potential therapeutic application

Highly selective inhibition of myosin motors provides the basis of potential therapeutic application

New roles of filopodia and podosomes in the differentiation and fusion process of osteoclasts

Filopodia are dispensable for endothelial tip cell guidance

Contact Info

Product

Resources

About