title: Focal adhesion kinase promotes integrin adhesion dynamics necessary for chemotropic turning of nerve growth cones.
abstract: The ability of extending axons to navigate using combinations of extracellular cues is essential for proper neural network formation. One intracellular signaling molecule that integrates convergent signals from both extracellular matrix (ECM) proteins and growth factors is focal adhesion kinase (FAK). Analysis of FAK function shows that it influences a variety of cellular activities, including cell motility, proliferation, and differentiation. Recent work in developing neurons has shown that FAK and Src function downstream of both attractive and repulsive growth factors, but little is known about the effectors or cellular mechanisms that FAK controls in growth cones on ECM proteins. We report that FAK functions downstream of brain-derived neurotrophic factor (BDNF) and laminin in the modulation of point contact dynamics, phosphotyrosine signaling at filopodial tips, and lamellipodial protrusion. BDNF stimulation accelerates paxillin-containing point contact turnover and formation. Knockdown of FAK function either with a FAK antisense morpholino or by expression of FRNK, a dominant-negative FAK isoform, blocks all aspects of the response to BDNF, including the acceleration of point contact dynamics. On the other hand, expression of specific FAK point mutants can selectively disrupt distinct aspects of the response to BDNF. We also show that growth cone turning depends on both signaling cascades tested here. Finally, we provide the first evidence that growth cone point contacts are asymmetrically regulated during turning to an attractive guidance cue.
authors.affiliation: Department of Neuroscience, University of Wisconsin, Madison, Wisconsin 53706, USA.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Myers
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Gomez
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology; D002478:Cells, Cultured; D002633:Chemotaxis / Q000235:genetics / Q000502:physiology*; D004625:Embryo, Nonmammalian; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D022001:Focal Adhesions / Q000378:metabolism; D055785:Gene Knockdown Techniques / Q000379:methods; D020439:Growth Cones / Q000187:drug effects / Q000502:physiology*; D009154:Mutation; D016376:Oligonucleotides, Antisense / Q000235:genetics; D051419:Paxillin / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000502:physiology; D011554:Pseudopodia / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D014982:Xenopus laevis; D019061:src-Family Kinases / Q000378:metabolism / Q000502:physiology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D016376:Oligonucleotides, Antisense; D051419:Paxillin; D019000:Phosphotyrosine; C113183:FAK-related nonkinase; D011505:Protein-Tyrosine Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019061:src-Family Kinases