FBW7 suppresses cell proliferation and G2/M cell cycle transition via promoting γ-catenin K63-linked ubiquitylation

Area of Science:

• Oncogenic signaling pathways
• Ubiquitin ligase function
• Cell cycle regulation

Background:

• FBW7 is an E3 ubiquitin ligase frequently mutated in cancer, typically targeting proteins for degradation.
• Its role in non-degradable ubiquitin signaling, particularly K63-linked ubiquitylation, in cancer remains largely uncharacterized.
• SCF-FBW7 complexes usually mediate K11 or K48-linked ubiquitylation for substrate degradation.

Purpose of the Study:

• To investigate the role of FBW7 in non-degradable ubiquitin signaling in human cancers.
• To identify novel binding partners of FBW7 and elucidate their functional relationship.
• To understand the mechanism by which FBW7 influences cell cycle and proliferation.

Main Methods:

• Tandem affinity purification coupled with mass spectrometry (TAP-MS) to identify FBW7 binding proteins.
• Western blotting to assess protein stability and ubiquitylation levels.
• Gene knockdown and rescue experiments to confirm functional roles.

Main Results:

• γ-catenin was identified as a novel binding partner of FBW7.
• FBW7 knockdown reduced K63-linked ubiquitylation of γ-catenin without affecting its stability.
• This reduction led to decreased expression of the γ-catenin downstream gene 14-3-3σ.
• FBW7 and γ-catenin cooperate to inhibit G2/M cell cycle transition and tumor cell proliferation.

Conclusions:

• FBW7 promotes K63-linked ubiquitylation of γ-catenin, a novel non-degradative function.
• This FBW7-γ-catenin axis plays a crucial role in inhibiting G2/M cell cycle progression.
• The findings provide new insights into FBW7's tumor-suppressive functions beyond protein degradation.