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Mutations of Ros differentially effecting signal transduction pathways leading to cell growth versus transformation

C S Zong1, J L Chan, S K Yang

  • 1Department of Microbiology, Mount Sinai School of Medicine, New York, New York 10029, USA.

The Journal of Biological Chemistry
|January 17, 1997
PubMed

Insights

Mutations in the v-Ros protein-tyrosine kinase reveal key signaling roles. Specific mutations reduce oncogenicity by impairing v-Ros interactions with IRS-1 and cytoskeletal proteins.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • The oncogenic protein-tyrosine kinase v-Ros plays a critical role in cell signaling and cancer development.
  • Understanding the specific functions of v-Ros tyrosine residues is crucial for deciphering its oncogenic mechanisms.

Purpose of the Study:

  • To investigate the signaling functions of v-Ros by systematically mutating tyrosine residues in its cytoplasmic domain.
  • To identify specific v-Ros residues and motifs critical for its kinase activity, oncogenicity, and downstream signaling pathways.

Main Methods:

  • Systematic mutation of tyrosine residues in the v-Ros cytoplasmic domain.
  • Analysis of v-Ros autophosphorylation, interaction with phospholipase Cgamma, and kinase activity.
  • Assessment of Ras/MAPK pathway activation, IRS-1 phosphorylation, and interaction with PI3K.
  • Evaluation of tyrosine phosphorylation of cytoskeletal and cell-cell interacting proteins.
  • Assay of mitogenic and oncogenic activities of v-Ros mutants.

Main Results:

  • Mutation of Tyr-564 significantly inhibited v-Ros autophosphorylation and phospholipase Cgamma interaction.
  • A cluster of tyrosine residues (Tyr-414, Tyr-418, Tyr-419) within the PTK domain modulated v-Ros kinase activity.
  • Mutant F419 and DI retained wild-type kinase and mitogenic activities but showed reduced oncogenicity.
  • F419 mutant failed to phosphorylate IRS-1 or promote IRS-1/PI3K association, suggesting a novel IRS-1 recognition site.
  • Both F419 and DI mutants exhibited impaired tyrosine phosphorylation of cytoskeletal and cell-cell interacting proteins, correlating with reduced transforming ability.

Conclusions:

  • Specific tyrosine residues in v-Ros are critical for its oncogenic functions.
  • The F419 mutation highlights a novel v-Ros recognition site for IRS-1, impacting PI3K signaling.
  • Impairment of v-Ros signaling to the cytoskeleton, mediated by residues like F419, significantly reduces its cell-transforming ability.

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