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The FAK-Arp2/3 interaction promotes leading edge advance and haptosensing by coupling nascent adhesions to lamellipodia actin

Swaminathan, Vinay LU ; Fischer, R S and Waterman, Clare M (2016) In Molecular Biology of the Cell 27(7). p.1085-1100
Abstract

Cell migration is initiated in response to biochemical or physical cues in the environment that promote actin-mediated lamellipodial protrusion followed by the formation of nascent integrin adhesions (NAs) within the protrusion to drive leading edge advance. Although FAK is known to be required for cell migration through effects on focal adhesions, its role in NA formation and lamellipodial dynamics is unclear. Live-cell microscopy of FAK(-/-)cells with expression of phosphorylation deficient or a FERM-domain mutant deficient in Arp2/3 binding revealed a requirement for FAK in promoting the dense formation, transient stabilization, and timely turnover of NA within lamellipodia to couple actin-driven protrusion to adhesion and advance of... (More)

Cell migration is initiated in response to biochemical or physical cues in the environment that promote actin-mediated lamellipodial protrusion followed by the formation of nascent integrin adhesions (NAs) within the protrusion to drive leading edge advance. Although FAK is known to be required for cell migration through effects on focal adhesions, its role in NA formation and lamellipodial dynamics is unclear. Live-cell microscopy of FAK(-/-)cells with expression of phosphorylation deficient or a FERM-domain mutant deficient in Arp2/3 binding revealed a requirement for FAK in promoting the dense formation, transient stabilization, and timely turnover of NA within lamellipodia to couple actin-driven protrusion to adhesion and advance of the leading edge. Phosphorylation on Y397 of FAK promotes dense NA formation but is dispensable for transient NA stabilization and leading edge advance. In contrast, transient NA stabilization and advance of the cell edge requires FAK-Arp2/3 interaction, which promotes Arp2/3 localization to NA and reduces FAK activity. Haptosensing of extracellular matrix (ECM) concentration during migration requires the interaction between FAK and Arp2/3, whereas FAK phosphorylation modulates mechanosensing of ECM stiffness during spreading. Taken together, our results show that mechanistically separable functions of FAK in NA are required for cells to distinguish distinct properties of their environment during migration.

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author
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Actin-Related Protein 2-3 Complex/metabolism, Actins, Animals, Cell Movement, Extracellular Matrix/metabolism, Fibroblasts/metabolism, Focal Adhesion Kinase 1/metabolism, Focal Adhesions/metabolism, Integrins, Mice, Phosphorylation, Protein Binding, Pseudopodia/metabolism
in
Molecular Biology of the Cell
volume
27
issue
7
pages
1085 - 1100
publisher
American Society for Cell Biology
external identifiers
  • scopus:84962361595
ISSN
1939-4586
DOI
10.1091/mbc.E15-08-0590
language
English
LU publication?
no
id
befd71b8-1ab7-4472-bcb8-72fb5e9876b8
date added to LUP
2018-09-07 16:50:36
date last changed
2018-09-23 04:59:07
@article{befd71b8-1ab7-4472-bcb8-72fb5e9876b8,
  abstract     = {<p>Cell migration is initiated in response to biochemical or physical cues in the environment that promote actin-mediated lamellipodial protrusion followed by the formation of nascent integrin adhesions (NAs) within the protrusion to drive leading edge advance. Although FAK is known to be required for cell migration through effects on focal adhesions, its role in NA formation and lamellipodial dynamics is unclear. Live-cell microscopy of FAK(-/-)cells with expression of phosphorylation deficient or a FERM-domain mutant deficient in Arp2/3 binding revealed a requirement for FAK in promoting the dense formation, transient stabilization, and timely turnover of NA within lamellipodia to couple actin-driven protrusion to adhesion and advance of the leading edge. Phosphorylation on Y397 of FAK promotes dense NA formation but is dispensable for transient NA stabilization and leading edge advance. In contrast, transient NA stabilization and advance of the cell edge requires FAK-Arp2/3 interaction, which promotes Arp2/3 localization to NA and reduces FAK activity. Haptosensing of extracellular matrix (ECM) concentration during migration requires the interaction between FAK and Arp2/3, whereas FAK phosphorylation modulates mechanosensing of ECM stiffness during spreading. Taken together, our results show that mechanistically separable functions of FAK in NA are required for cells to distinguish distinct properties of their environment during migration. </p>},
  author       = {Swaminathan, Vinay and Fischer, R S and Waterman, Clare M},
  issn         = {1939-4586},
  keyword      = {Actin-Related Protein 2-3 Complex/metabolism,Actins,Animals,Cell Movement,Extracellular Matrix/metabolism,Fibroblasts/metabolism,Focal Adhesion Kinase 1/metabolism,Focal Adhesions/metabolism,Integrins,Mice,Phosphorylation,Protein Binding,Pseudopodia/metabolism},
  language     = {eng},
  month        = {04},
  number       = {7},
  pages        = {1085--1100},
  publisher    = {American Society for Cell Biology},
  series       = {Molecular Biology of the Cell},
  title        = {The FAK-Arp2/3 interaction promotes leading edge advance and haptosensing by coupling nascent adhesions to lamellipodia actin},
  url          = {http://dx.doi.org/10.1091/mbc.E15-08-0590},
  volume       = {27},
  year         = {2016},
}