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Analysis of Cell Cycle Position in Mammalian Cells
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FAK-mediated phosphorylation at Y464 regulates p85β nuclear translocation to promote tumorigenesis of ccRCC by

Yanhua Zhang1, Baoyu He2, Dong Zhang1

  • 1State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.

Cell Reports
|March 1, 2023
PubMed

Insights

Nuclear p85β promotes kidney cancer by interacting with KPNA1 and repressing RB1. Targeting FAK with defactinib may treat ccRCC, especially in patients with high p85β Y464 levels.

Area of Science:

  • Molecular Biology
  • Oncology
  • Cell Biology

Background:

  • Phosphatidylinositol 3-kinase (PI3K) regulatory subunit p85s typically stabilizes the catalytic subunit p110s in the cytoplasm.
  • Emerging evidence highlights crucial roles for nucleus-localized, p110-free p85s in cellular functions.
  • Mechanisms governing nuclear translocation of p85s remain largely uncharacterized.

Purpose of the Study:

  • To elucidate the mechanism of p85β nuclear translocation.
  • To investigate the role of nuclear p85β in clear cell renal cell carcinoma (ccRCC) tumorigenesis.
  • To identify potential therapeutic targets for ccRCC based on p85β function.

Main Methods:

  • Investigated p85β nuclear translocation mechanism using phosphorylation site analysis and protein-protein interaction studies.
  • Assessed PIK3R2/p85β expression in ccRCC patient samples and correlated with survival data.
  • Examined the oncogenic functions of nuclear p85β, including its effects on RB1 expression and cell cycle regulation.
  • Studied the interaction of nuclear p85β with histone methyltransferases EZH1/EZH2.
  • Evaluated the efficacy of FAK inhibitor defactinib in ccRCC models.

Main Results:

  • Phosphorylation of p85β at Y464 by FAK enhances its binding to KPNA1, facilitating nuclear translocation in kidney cells.
  • PIK3R2/p85β is overexpressed in ccRCC and linked to poorer patient survival.
  • Nuclear p85β, not cytoplasmic, drives oncogenesis by suppressing RB1 expression and altering G1/S cell cycle transition.
  • Nuclear p85β stabilizes EZH1/EZH2, key histone methyltransferases, to repress RB1.
  • Defactinib treatment significantly inhibited ccRCC tumor growth in models with elevated p85β Y464.

Conclusions:

  • FAK-mediated phosphorylation of p85β at Y464 is a key driver of its nuclear import.
  • Nuclear p85β acts as an oncoprotein in ccRCC by disrupting cell cycle control via RB1 repression.
  • Targeting FAK with defactinib presents a promising therapeutic strategy for ccRCC, particularly in tumors with high p85β Y464.
Keywords:
CP: CancerFAKRB1ccRCCnuclear translocationp85βtyrosine phosphorylation

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