Requirement of both tyrosine residues 1330 and 1337 in the C-terminal tail of the RON receptor tyrosine kinase for epithelial cell scattering and migration.
RON is a receptor tyrosine kinase that mediates cell scattering, migration, and tubular formation. This study focused on the function of two tyrosines, Y1330 and Y1337, in the C-terminus of RON in regulating epithelial cell scattering and migration. Substitution of both tyrosine residues with phenylalanine causes complete loss of cell scattering and migration in kidney 293 cells. In contrast, single mutation of either tyrosine residue has no effect. We found that mutation at Y1330 or Y1337 alone does not significantly affect the association of RON with PI-3 kinase, whereas a double mutation abolishes the recruitment of substrates. RON-mediated cell migration was inhibited by PI-3 kinase inhibitor wortmannin. This effect was also achieved by a dominant inhibitory p85 of PI-3 kinase. We conclude that Y1330 and Y1337 are required for RON-mediated cell motility. By associating with PI-3 kinase, the Y1330-Y1337 docking site plays a critical role in transducing motile signals of RON.
Xiao
Z Q
ZQ
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine and Denver Health Medical Center, Denver, Colorado 80204, USA.
Chen
Y Q
YQ
Wang
M H
MH
D019943:Amino Acid Substitution; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000502:physiology; D015870:Gene Expression; D006801:Humans; D051379:Mice; D016297:Mutagenesis, Site-Directed; D010446:Peptide Fragments / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011817:Rabbits; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D014443:Tyrosine / Q000737:chemistry; D000077191:Wortmannin
D000730:Androstadienes; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020794:Receptor Protein-Tyrosine Kinases; D011956:Receptors, Cell Surface; D014443:Tyrosine; D000077191:Wortmannin; C080835:RON protein