title: Spontaneous phosphoinositide 3-kinase signaling dynamics drive spreading and random migration of fibroblasts.
abstract: During directed cell migration (chemotaxis), cytoskeletal dynamics are stimulated and spatially biased by phosphoinositide 3-kinase (PI3K) and other signal transduction pathways. Live-cell imaging using total internal reflection fluorescence (TIRF) microscopy revealed that, in the absence of soluble cues, 3'-phosphoinositides are enriched in a localized and dynamic fashion during active spreading and random migration of mouse fibroblasts on adhesive surfaces. Surprisingly, we found that PI3K activation is uncoupled from classical integrin-mediated pathways and feedback from the actin cytoskeleton. Inhibiting PI3K significantly impairs cell motility, both in the context of normal spreading and when microtubules are dissociated, which induces a dynamic protrusion phenotype as seen by TIRF in our cells. Accordingly, during random migration, 3'-phosphoinositides are frequently localized to regions of membrane protrusion and correlate quantitatively with the direction and persistence of cell movement. These results underscore the importance of localized PI3K signaling not only in chemotaxis but also in basal motility/migration of fibroblasts.
authors.affiliation: Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC 27695, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Weiger
authors.forename: Chun-Chao
authors.initials: CC
authors.lastname: Wang
authors.forename: Matej
authors.initials: M
authors.lastname: Krajcovic
authors.forename: Adam T
authors.initials: AT
authors.lastname: Melvin
authors.forename: John J
authors.initials: JJ
authors.lastname: Rhoden
authors.forename: Jason M
authors.initials: JM
authors.lastname: Haugh
mesh_terms: D000199:Actins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D002633:Chemotaxis / Q000502:physiology*; D015638:Cytochalasin D / Q000494:pharmacology; D003599:Cytoskeleton / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D011554:Pseudopodia / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000199:Actins; D010982:Platelet-Derived Growth Factor; D015638:Cytochalasin D; D019869:Phosphatidylinositol 3-Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D051416:Focal Adhesion Protein-Tyrosine Kinases