Netrin requires focal adhesion kinase and Src family kinases for axon outgrowth and attraction.
Although netrins are an important family of neuronal guidance proteins, intracellular mechanisms that mediate netrin function are not well understood. Here we show that netrin-1 induces tyrosine phosphorylation of proteins including focal adhesion kinase (FAK) and the Src family kinase Fyn. Blockers of Src family kinases inhibited FAK phosphorylation and axon outgrowth and attraction by netrin. Dominant-negative FAK and Fyn mutants inhibited the attractive turning response to netrin. Axon outgrowth and attraction induced by netrin-1 were significantly reduced in neurons lacking the FAK gene. Our results show the biochemical and functional links between netrin, a prototypical neuronal guidance cue, and FAK, a central player in intracellular signaling that is crucial for cell migration.
Liu
Guofa
G
Department of Anatomy, Washington University School of Medicine, 660 South Euclid Ave., St. Louis, Missouri 63110, USA.
Beggs
Hilary
H
Jürgensen
Claudia
C
Park
Hwan-Tae
HT
Tang
Hao
H
Gorski
Jessica
J
Jones
Kevin R
KR
Reichardt
Louis F
LF
Wu
Jane
J
Rao
Yi
Y
D000704:Analysis of Variance; D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D048429:Cell Size; D000089622:Doublecortin Domain Proteins; D015774:Ganciclovir / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D019426:Integrases / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D039842:Neural Cell Adhesion Molecule L1 / Q000378:metabolism; D009457:Neuroglia / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D009479:Neuropeptides / Q000378:metabolism; D009830:Olfactory Bulb / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D016548:Prosencephalon / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D012794:Sialic Acids / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology*; D013937:Thymidine Kinase / Q000235:genetics; D014404:Tubulin / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
D000089622:Doublecortin Domain Proteins; D005904:Glial Fibrillary Acidic Protein; D008869:Microtubule-Associated Proteins; D039842:Neural Cell Adhesion Molecule L1; D009479:Neuropeptides; D012794:Sialic Acids; D014404:Tubulin; C462941:beta3 tubulin, mouse; C103469:polysialyl neural cell adhesion molecule; D049452:Green Fluorescent Proteins; D013937:Thymidine Kinase; C045073:Cre recombinase; D019426:Integrases; D001616:beta-Galactosidase; D010751:Phosphopyruvate Hydratase; D001973:Bromodeoxyuridine; D015774:Ganciclovir