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Oncogenic RET kinase domain mutations perturb the autophosphorylation trajectory by enhancing substrate presentation

Iván Plaza-Menacho1, Karin Barnouin2, Kerry Goodman1

  • 1Structural Biology Laboratory, London Research Institute, Cancer Research UK, WC2A 3LY London, UK.

Molecular Cell
|February 25, 2014
PubMed

Insights

Oncogenic RET kinase mutations accelerate autophosphorylation by improving intermolecular substrate presentation, revealing a new mechanism for cancer development. This study clarifies RET kinase activation and deregulation.

Area of Science:

  • Molecular biology
  • Biochemistry
  • Cancer research

Background:

  • RET kinase is crucial in development and cancer.
  • Understanding RET kinase activation and oncogenic deregulation is key to targeted therapies.

Purpose of the Study:

  • To elucidate the molecular mechanisms of RET kinase activation and oncogenic deregulation.
  • To define the temporal sequence of RET autophosphorylation and its modulation by oncogenic mutations.

Main Methods:

  • Label-free quantitative mass spectrometry to determine temporal autophosphorylation sites.
  • Biochemical assays to assess enzymatic activity and ATP affinity.
  • Structural analysis of wild-type and oncogenic RET kinase domains.

Main Results:

  • Early autophosphorylation sites are distinct from late sites within the activation loop.
  • Oncogenic RET kinase exhibits enhanced enzymatic activity, increased ATP affinity, and improved intermolecular substrate presentation.
  • Structural analysis revealed a cis-inhibitory mechanism involving specific loop and helix contacts in wild-type RET.
  • Tether mutations mimicked oncogenic effects on autophosphorylation trajectory by altering substrate presentation.

Conclusions:

  • Oncogenic RET kinase mutations promote intermolecular autophosphorylation by enhancing substrate presentation.
  • A cis-inhibitory mechanism regulates wild-type RET kinase activity.
  • These findings offer new insights into RET-driven oncogenesis and potential therapeutic strategies.

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