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Two diphosphorylated degrons control c-Myc degradation by the Fbw7 tumor suppressor

Markus Welcker1,2, Baiyun Wang3,4, Domniţa-Valeria Rusnac3,4

  • 1Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.

Science Advances
|January 28, 2022
PubMed

Insights

Researchers discovered a second critical site on the c-Myc protein (Myc) that helps control its degradation. This finding reveals new insights into how Myc drives cancer and suggests novel therapeutic strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • c-Myc is a crucial cancer driver protein.
  • Its stability is regulated by the SCFFbw7 ubiquitin ligase and proteasomal degradation.
  • Mutations in Fbw7 or Myc's threonine 58 (T58) residue impair Myc degradation, contributing to cancer.

Purpose of the Study:

  • To identify and characterize novel regulatory mechanisms of c-Myc degradation.
  • To elucidate the role of phosphorylation at Myc T244 in Fbw7-mediated degradation.
  • To understand the interplay between different Myc phosphodegrons and their impact on cancer.

Main Methods:

  • Biochemical assays to study Myc ubiquitylation and degradation.
  • Site-directed mutagenesis to investigate the role of specific phosphorylation sites.
  • Crystallographic studies to determine the structural basis of Fbw7-Myc interaction.
  • Analysis of cancer mutation data related to Fbw7 and Myc.

Main Results:

  • A second Fbw7 phosphodegron at Myc T244 was identified, essential for Myc ubiquitylation and degradation.
  • Contrary to previous assumptions, serine 62 phosphorylation (pS62) enhances Fbw7 binding, forming a high-affinity degron.
  • Both T58 and T244 degrons bind Fbw7 in their diphosphorylated forms.
  • The T244 degron utilizes a unique binding mode involving Fbw7 arginine 689 (R689), a cancer-associated mutational hotspot.

Conclusions:

  • Myc degradation is regulated by at least two distinct Fbw7 phosphodegrons (T58 and T244).
  • Phosphorylation at pS62 is integral to a high-affinity Myc degron, promoting rather than inhibiting Fbw7 binding.
  • The unique recognition of the T244 degron by Fbw7 R689 offers new avenues for therapeutic intervention.
  • These findings provide critical insights into Myc-driven tumorigenesis and strategies for targeting Myc stability.

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