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Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays
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A tyrosine protein kinase activated by bombesin in normal fibroblasts and small cell carcinomas

G Gaudino1, M Cilli, L Gandino

  • 1Department of Biomedical Sciences and Oncology, University of Torino Medical School, Italy.

Annals of the New York Academy of Sciences
|January 1, 1988
PubMed

Insights

Bombesin stimulation causes tyrosine phosphorylation of a 115-kDa protein (p115) in fibroblasts, preceding gene activation and promoting cell growth. This protein is also phosphorylated in small cell lung cancer cells, suggesting autocrine signaling.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Oncology

Background:

  • Antibodies recognizing phosphotyrosine (P-Tyr) identify a 115-kDa cell surface protein (p115).
  • Bombesin stimulation of quiescent cells induces tyrosine phosphorylation of p115.
  • This phosphorylation correlates with the mitogenic effect of bombesin.

Purpose of the Study:

  • To investigate the role of p115 tyrosine phosphorylation in bombesin-induced mitogenesis.
  • To examine p115 phosphorylation in human small cell lung carcinoma (SCLC) cells.
  • To explore the hypothesis of autocrine bombesin receptor activation in SCLC.

Main Methods:

  • Using P-Tyr antibodies to detect and immunoprecipitate p115.
  • Measuring [3H]thymidine incorporation to assess mitogenic effects.
  • Performing immunocomplex kinase assays to determine tyrosine kinase activity.
  • Analyzing p115 phosphorylation in SCLC lines with and without bombesin production.

Main Results:

  • Bombesin stimulation dose-dependently increased p115 tyrosine phosphorylation, preceding c-fos and c-myc gene activation.
  • Immunocomplexes of phosphorylated p115 specifically bound [Tyr4]bombesin and showed enhanced tyrosine protein kinase activity.
  • A 115-kDa tyrosine-phosphorylated protein was detected in bombesin-producing SCLC lines but not in a non-producer variant.
  • SCLC p115 exhibited intrinsic tyrosine protein kinase activity, independent of exogenous bombesin.

Conclusions:

  • p115 tyrosine phosphorylation is a key event in bombesin-induced mitogenesis.
  • The presence and activity of p115 in SCLC cells support the hypothesis of autocrine bombesin receptor activation.
  • p115 may represent a potential therapeutic target in SCLC.

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