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AGO2 phosphorylation by c-Src kinase promotes tumorigenesis

Tianqi Liu1, Hailong Zhang1, Jiayu Fang1

  • 1Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025, China.

Neoplasia (New York, N.Y.)
|January 26, 2020
PubMed

Insights

The study reveals that c-Src kinase phosphorylates AGO2, a key protein in RNA interference, impacting tumor progression. This phosphorylation affects microRNA maturation and promotes tumor growth, highlighting a potential therapeutic target.

Area of Science:

  • Molecular Biology
  • Oncology
  • Biochemistry

Background:

  • c-Src tyrosine kinase is frequently overexpressed in various tumors.
  • The role of c-Src in the microRNA (miRNA) pathway remains largely uncharacterized.
  • AGO2 is a crucial component of the RNA-induced silencing complex (RISC).

Purpose of the Study:

  • To investigate the interaction between c-Src and AGO2.
  • To determine if c-Src influences the miRNA pathway through AGO2.
  • To elucidate the functional consequences of c-Src-mediated AGO2 phosphorylation in cancer.

Main Methods:

  • Co-immunoprecipitation to assess protein interactions.
  • Western blotting with phospho-specific antibodies to detect phosphorylation sites.
  • In vitro and in vivo assays to evaluate tumor-promoting effects.
  • Treatment with c-Src kinase inhibitor Saracatinib.

Main Results:

  • c-Src directly interacts with and phosphorylates AGO2 at tyrosine residues 393, 529, and 749.
  • Phosphorylation of AGO2 at tyr393 by c-Src inhibits the maturation of pre-miR-192 by reducing DICER binding.
  • Ectopic expression of wild-type AGO2, but not its tyrosine mutants, promotes tumor growth in vitro and in vivo.
  • The tumor-promoting effect of AGO2 is abrogated by Saracatinib treatment.

Conclusions:

  • AGO2 is identified as a direct target of c-Src kinase.
  • c-Src-mediated phosphorylation of AGO2, particularly at tyr393, plays a significant role in suppressing miRNA maturation and promoting tumor progression.
  • Targeting the c-Src-AGO2 interaction or c-Src activity may represent a novel therapeutic strategy in cancer.
Keywords:
SaracatinibTumorigenesisTyrosine phosphorylationc-Src, AGO2

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