A1 Refereed original research article in a scientific journal
alpha 5 beta 1 integrin recycling promotes Arp2/3-independent cancer cell invasion via the formin FHOD3
Authors: Paul NR, Allen JL, Chapman A, Morlan-Mairal M, Zindy E, Jacquemet G, del Ama LF, Ferizovic N, Green DM, Howe JD, Ehler E, Hurlstone A, Caswell PT
Publisher: ROCKEFELLER UNIV PRESS
Publication year: 2015
Journal: Journal of Cell Biology
Journal name in source: JOURNAL OF CELL BIOLOGY
Journal acronym: J CELL BIOL
Volume: 210
Issue: 6
First page : 1013
Last page: 1031
Number of pages: 19
ISSN: 0021-9525
eISSN: 1540-8140
DOI: https://doi.org/10.1083/jcb.201502040
Invasive migration in 3D extracellular matrix (ECM) is crucial to cancer metastasis, yet little is known of the molecular mechanisms that drive reorganization of the cytoskeleton as cancer cells disseminate in vivo. 2D Rac-driven lamellipodial migration is well understood, but how these features apply to 3D migration is not clear. We find that lamellipodia-like protrusions and retrograde actin flow are indeed observed in cells moving in 3D ECM. However, Rab-coupling protein (RCP)-driven endocytic recycling of alpha 5 beta 1 integrin enhances invasive migration of cancer cells into fibronectin-rich 3D ECM, driven by RhoA and filopodial spike-based protrusions, not lamellipodia. Furthermore, we show that actin spike protrusions are Arp2/3-independent. Dynamic actin spike assembly in cells invading in vitro and in vivo is regulated by Formin homology-2 domain containing 3 (FHOD3), which is activated by RhoA/ROCK, establishing a novel mechanism through which the RCP-alpha 5 beta 1 pathway reprograms the actin cytoskeleton to promote invasive migration and local invasion in vivo.
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