Abstract
Netrins are a family of secreted molecules that are important for axonal outgrowth and guidance in the developing nervous system. However, the signaling mechanisms that lie immediately downstream of netrin receptors remain poorly understood. Here we report that the netrin receptor DCC (deleted in colorectal cancer) interacts with the focal adhesion kinase (FAK), a kinase implicated in regulating cell adhesion and migration. FAK was expressed in developing brains and was localized with DCC in cultured neurons. Netrin-1 induced FAK and DCC tyrosine phosphorylation. Disruption of FAK signaling abolished netrin-1-induced neurite outgrowth and attractive growth cone turning. Taken together, these results indicate a new signaling mechanism for DCC, in which FAK is activated upon netrin-1 stimulation and mediates netrin-1 function; they also identify a critical role for FAK in axon navigation.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Axons / drug effects
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Axons / physiology*
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Blotting, Western / methods
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Cell Count
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Cells, Cultured
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Cerebral Cortex / cytology
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Chick Embryo
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Coculture Techniques / methods
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Culture Media, Conditioned / pharmacology
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Dose-Response Relationship, Drug
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Drug Interactions
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Embryo, Mammalian
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Enzyme Activation / drug effects
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Enzyme Inhibitors / pharmacology
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Female
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Focal Adhesion Kinase 1
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Focal Adhesion Protein-Tyrosine Kinases
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Gene Expression Regulation
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Green Fluorescent Proteins / metabolism
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Humans
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Immunohistochemistry / methods
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Immunoprecipitation / methods
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Laminin / pharmacology
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Male
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Mice
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Mice, Knockout
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Mucoproteins / pharmacology
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Nerve Growth Factor / pharmacology
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Nerve Growth Factors / pharmacology
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Nerve Growth Factors / physiology*
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Netrin-1
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Neurites / drug effects
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Neurites / physiology*
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Neurons / drug effects
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Neurons / metabolism
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Oncogene Proteins v-abl / metabolism
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Phosphorylation / drug effects
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Pregnancy
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism*
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Rats
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Receptor, trkA / metabolism
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Spinal Cord / metabolism
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Time Factors
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Tubulin / metabolism
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Tumor Suppressor Proteins
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Two-Hybrid System Techniques
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Tyrosine / metabolism
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src-Family Kinases / metabolism
Substances
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Culture Media, Conditioned
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Enzyme Inhibitors
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Laminin
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Mucoproteins
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NTN1 protein, human
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Nerve Growth Factors
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Ntn1 protein, mouse
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Ntn1 protein, rat
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Oncogene Proteins v-abl
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Tubulin
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Tumor Suppressor Proteins
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beta3 tubulin, mouse
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lysin, gastropoda
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Green Fluorescent Proteins
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Netrin-1
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Tyrosine
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Nerve Growth Factor
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Protein-Tyrosine Kinases
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Receptor, trkA
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Focal Adhesion Kinase 1
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Focal Adhesion Protein-Tyrosine Kinases
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PTK2 protein, human
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Ptk2 protein, mouse
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Ptk2 protein, rat
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src-Family Kinases