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Ret-mediated mitogenesis requires Src kinase activity

R M Melillo1, M V Barone, G Lupoli

  • 1Centro di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche, Dipartimento di Biologia e Patologia Cellulare e Molecolare, Facoltà di Medicina e Chirurgia di Napoli, Università di Napoli Federico II, Naples, Italy.

Cancer Research
|March 10, 1999
PubMed

Insights

The proto-oncogene RET receptor tyrosine kinase (RTK) activates Src kinase, which is crucial for cell growth. RET mutations increase Src activity, contributing to diseases like thyroid cancer.

Area of Science:

  • Molecular Biology
  • Oncology
  • Cell Signaling

Background:

  • The proto-oncogene RET encodes a receptor tyrosine kinase (RTK) implicated in various human diseases.
  • Activation of RTKs leads to downstream signaling cascades involving nonreceptor tyrosine kinases, such as Src family kinases.
  • Understanding the interplay between RET and Src is vital for deciphering cancer development and progression.

Purpose of the Study:

  • To investigate the role of c-Src in RET-mediated signaling pathways.
  • To determine if RET activation leads to c-Src activation.
  • To assess the necessity of Src kinase activity for RET-induced mitogenesis.

Main Methods:

  • Coexpression of RET and accessory receptors in NIH3T3 cells.
  • Stimulation with glial cell line-derived neurotrophic factor or epidermal growth factor.
  • Measurement of c-Src kinase activity and RET-Src association.
  • Microinjection of kinase-inactive c-Src mutants.

Main Results:

  • RET stimulation activated c-Src kinase.
  • Mutated RET isoforms exhibited elevated Src kinase activity.
  • RET associated with Src in a phosphotyrosine-dependent manner.
  • Inhibition of c-Src blocked RET-mediated mitogenic effects.

Conclusions:

  • Activated RET directly binds and stimulates c-Src kinase.
  • Src kinase activation is essential for the mitogenic signaling initiated by RET.
  • These findings highlight a critical molecular mechanism in RET-driven oncogenesis.

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