Mutations of Ros differentially effecting signal transduction pathways leading to cell growth versus transformation.
The signaling functions of the oncogenic protein-tyrosine kinase v-Ros were studied by systematically mutating the tyrosine residues in its cytoplasmic domain. The carboxyl mutation of Tyr-564 produces the most pronounced inhibitory effect on v-Ros autophosphorylation and interaction with phospholipase Cgamma. A cluster of 3 tyrosine residues, Tyr-414, Tyr-418, and Tyr-419, within the PTK domain of v-Ros plays an important role in modulating its kinase activity. The mutant F419 and the mutant DI, deleting 6-amino acids near the catalytic loop, retain wild type protein tyrosine kinase and mitogenic activities, but have dramatically reduced oncogenicity. Both mutant proteins are able to phosphorylate or activate components in the Ras/microtubule-associated protein kinase signaling pathway. However, F419 mutant protein is unable to phosphorylate insulin receptor substrate 1 (IRS-1) or promote association of IRS-1 with phosphatidylinositol 3-kinase. This tyrosine residue in the context of the NDYY motif may define a novel recognition site for IRS-1. Both F419 and DI mutants display impaired ability to induce tyrosine phosphorylation of a series of cytoskeletal and cell-cell interacting proteins. Thus the F419 and DI mutations define v-Ros sequences important for cytoskeleton signaling, the impairment of which correlates with the reduced cell transforming ability.
Zong
C S
CS
Department of Microbiology, Mount Sinai School of Medicine, New York, New York 10029, USA.
Chan
J L
JL
Yang
S K
SK
Wang
L H
LH
D000818:Animals; D002448:Cell Adhesion; D002455:Cell Division / Q000235:genetics; D002461:Cell Line, Transformed; D002642:Chick Embryo; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004789:Enzyme Activation; D055504:Insulin Receptor Substrate Proteins; D016297:Mutagenesis, Site-Directed; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases; D015398:Signal Transduction; D013379:Substrate Specificity
D003598:Cytoskeletal Proteins; D055504:Insulin Receptor Substrate Proteins; D009856:Oncogene Proteins, Viral; D010750:Phosphoproteins; D011494:Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; C058682:v-ros protein, Avian sarcoma virus UR2