Activation of FAK and Src are receptor-proximal events required for netrin signaling.
The axon guidance cue netrin is importantly involved in neuronal development. DCC (deleted in colorectal cancer) is a functional receptor for netrin and mediates axon outgrowth and the steering response. Here we show that different regions of the intracellular domain of DCC directly interacted with the tyrosine kinases Src and focal adhesion kinase (FAK). Netrin activated both FAK and Src and stimulated tyrosine phosphorylation of DCC. Inhibition of Src family kinases reduced DCC tyrosine phosphorylation and blocked both axon attraction and outgrowth of neurons in response to netrin. Mutation of the tyrosine phosphorylation residue in DCC abolished its function of mediating netrin-induced axon attraction. On the basis of our observations, we suggest a model in which DCC functions as a kinase-coupled receptor, and FAK and Src act immediately downstream of DCC in netrin signaling.
Li
Weiquan
W
Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.
Lee
Jeeyong
J
Vikis
Haris G
HG
Lee
Seung-Hee
SH
Liu
Guofa
G
Aurandt
Jennifer
J
Shen
Tang-Long
TL
Fearon
Eric R
ER
Guan
Jun-Lin
JL
Han
Min
M
Rao
Yi
Y
Hong
Kyonsoo
K
Guan
Kun-Liang
KL
D000818:Animals; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002460:Cell Line; D002645:Chickens; D000075389:DCC Receptor; D004347:Drug Interactions; D004622:Embryo, Mammalian; D004625:Embryo, Nonmammalian; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D020439:Growth Cones / Q000187:drug effects / Q000502:physiology; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D007814:Larva / Q000166:cytology; D008845:Microinjections / Q000379:methods; D016296:Mutagenesis / Q000502:physiology; D009414:Nerve Growth Factors / Q000378:metabolism* / Q000494:pharmacology; D000075388:Netrin-1; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D010766:Phosphorylation / Q000187:drug effects; D017434:Protein Structure, Tertiary / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D011956:Receptors, Cell Surface; D015398:Signal Transduction / Q000502:physiology*; D013116:Spinal Cord / Q000166:cytology; D013997:Time Factors; D014162:Transfection / Q000379:methods; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D014981:Xenopus; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
C412373:AG 1879; D015815:Cell Adhesion Molecules; D000075389:DCC Receptor; C501909:DCC protein, human; D004791:Enzyme Inhibitors; D009414:Nerve Growth Factors; D011743:Pyrimidines; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D019061:src-Family Kinases