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Docking protein FRS2 links the protein tyrosine kinase RET and its oncogenic forms with the mitogen-activated protein

R M Melillo1, M Santoro, S H Ong

  • 1Centro di Endocrinologia ed Oncologia Sperimentale del CNR, Dipartimento di Biologia e Patologia Cellulare e Molecolare, Naples, Italy.

Molecular and Cellular Biology
|June 8, 2001
PubMed

Insights

The docking protein FRS2 interacts with the RET receptor tyrosine kinase, mediating signaling. This interaction is crucial for both normal RET function and in diseases like MEN 2 and thyroid cancer.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Oncology

Background:

  • The RET receptor tyrosine kinase is vital for development and implicated in diseases.
  • Glial cell-derived neurotrophic factors (GDNF) are ligands for RET.
  • Mutations in RET are linked to Hirschsprung disease (HSCR), multiple endocrine neoplasia type 2 (MEN 2), and thyroid carcinomas.

Purpose of the Study:

  • To investigate the role of the docking protein FRS2 in RET signaling.
  • To determine how FRS2 interacts with both normal and oncogenic RET.
  • To elucidate FRS2's contribution to RET-mediated MAP kinase activation.

Main Methods:

  • Tyrosine phosphorylation assays to detect FRS2 interaction with RET.
  • Co-immunoprecipitation to confirm complex formation between RET and FRS2.
  • MAP kinase activation assays to assess signaling downstream of RET.

Main Results:

  • FRS2 is tyrosine phosphorylated by both ligand-stimulated and oncogenic RET.
  • FRS2 binds to RET at residue pY1062, forming a complex.
  • FRS2, but not Shc, potentiates MAP kinase activation by RET oncoproteins.
  • Oncogenic RET-PTC proteins constitutively associate with FRS2, leading to sustained signaling.
  • HSCR-associated RET mutants show reduced FRS2 binding and MAP kinase activation.

Conclusions:

  • FRS2 acts as a crucial adaptor protein, coupling both ligand-regulated and oncogenic RET to the MAP kinase signaling pathway.
  • FRS2 is essential for RET signal transduction in both normal physiological processes and pathological conditions like MEN 2 and thyroid cancer.

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