FAK and Src kinases are required for netrin-induced tyrosine phosphorylation of UNC5.
During neuronal development, netrin and its receptors UNC5 and DCC (deleted in colorectal cancer) guide axonal growth cones in navigating to their targets. Netrin also plays important roles in the regulation of cell migration, tissue morphogenesis and tumor growth. Here, we show that netrin induces UNC5 tyrosine phosphorylation and that this effect of netrin is dependent on its co-receptor DCC. UNC5 tyrosine phosphorylation is known to be important for netrin to induce cell migration and axonal repulsion. Src tyrosine kinase activity is required for netrin to stimulate UNC5 tyrosine phosphorylation in neurons and transfected cells. The SH2 domain of Src kinase directly interacts with the cytosolic domain of UNC5 in a tyrosine-phosphorylation-dependent manner. Furthermore, the tyrosine kinase focal adhesion kinase (FAK) is also involved in netrin-induced UNC5 tyrosine phosphorylation. Both Src and FAK can phosphorylate UNC5. Our data suggest a model in which netrin stimulates UNC5 tyrosine phosphorylation and signaling in a manner dependent on the co-receptor DCC, through the recruitment of Src and FAK kinases.
Li
Weiquan
W
Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA. wqli@umich.edu
Aurandt
Jennifer
J
Jürgensen
Claudia
C
Jürgense
Claudia
C
Rao
Yi
Y
Guan
Kun-Liang
KL
D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D000075388:Netrin-1; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism*; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
D029742:Caenorhabditis elegans Proteins; D009414:Nerve Growth Factors; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; C077588:UNC-5 protein, C elegans; D000075388:Netrin-1; D014443:Tyrosine; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019061:src-Family Kinases