Focal adhesion kinase modulates tension signaling to control actin and focal adhesion dynamics.
In response to alphabeta1 integrin signaling, transducers such as focal adhesion kinase (FAK) become activated, relaying to specific machineries and triggering distinct cellular responses. By conditionally ablating Fak in skin epidermis and culturing Fak-null keratinocytes, we show that FAK is dispensable for epidermal adhesion and basement membrane assembly, both of which require alphabeta1 integrins. FAK is also dispensible for proliferation/survival in enriched medium. In contrast, FAK functions downstream of alphabeta1 integrin in regulating cytoskeletal dynamics and orchestrating polarized keratinocyte migration out of epidermal explants. Fak-null keratinocytes display an aberrant actin cytoskeleton, which is tightly associated with robust, peripheral focal adhesions and microtubules. We find that without FAK, Src, p190RhoGAP, and PKL-PIX-PAK, localization and/or activation at focal adhesions are impaired, leading to elevated Rho activity, phosphorylation of myosin light chain kinase, and enhanced tensile stress fibers. We show that, together, these FAK-dependent activities are critical to control the turnover of focal adhesions, which is perturbed in the absence of FAK.
Schober
Markus
M
Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY 10021, USA.
Raghavan
Srikala
S
Nikolova
Maria
M
Polak
Lisa
L
Pasolli
H Amalia
HA
Beggs
Hilary E
HE
Reichardt
Louis F
LF
Fuchs
Elaine
E
D008841:Actin Cytoskeleton / Q000378:metabolism* / Q000648:ultrastructure; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D018929:Cell Culture Techniques; D002465:Cell Movement / Q000502:physiology; D048430:Cell Shape; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D051418:Focal Adhesion Kinase 2 / Q000032:analysis / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D022001:Focal Adhesions / Q000201:enzymology*; D020690:GTPase-Activating Proteins / Q000378:metabolism; D019012:Integrin beta1 / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D008870:Microtubules / Q000378:metabolism; D010766:Phosphorylation; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction
C513041:Arhgap35 protein, mouse; D004268:DNA-Binding Proteins; D020690:GTPase-Activating Proteins; D019012:Integrin beta1; D012097:Repressor Proteins; D051418:Focal Adhesion Kinase 2; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496053:Ptk2b protein, mouse