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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
Summary
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.
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