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Regulation of microRNA expression by the adaptor protein GRB2

Authors :
Stainthorp, Amy K
Lin, Chi-Chuan
Wang, Dapeng
Medhi, Ragini
Ahmed, Zamal
Suen, Kin Man
Miska, Eric A
Whitehouse, Adrian
Ladbury, John E
Apollo - University of Cambridge Repository
Publication Year :
2023
Publisher :
Springer Science and Business Media LLC, 2023.

Abstract

Protein interactions with the microRNA (miRNA)-mediated gene silencing protein Argonaute 2 (AGO2) control miRNA expression. miRNA biogenesis starts with the production of precursor transcripts and culminates with the loading of mature miRNA onto AGO2 by DICER1. Here we reveal an additional component to the regulatory mechanism for miRNA biogenesis involving the adaptor protein, growth factor receptor-bound protein 2 (GRB2). The N-terminal SH3 domain of GRB2 is recruited to the PAZ domain of AGO2 forming a ternary complex containing GRB2, AGO2 and DICER1. Using small-RNA sequencing we identified two groups of miRNAs which are regulated by the binding of GRB2. First, mature and precursor transcripts of mir-17~92 and mir-221 miRNAs are enhanced. Second, mature, but not precursor, let-7 family miRNAs are diminished suggesting that GRB2 directly affects loading of these miRNAs. Notably, the resulting loss of let-7 augments expression of oncogenic targets such as RAS. Thus, a new role for GRB2 is established with implications for cancer pathogenesis through regulation of miRNA biogenesis and oncogene expression.

Details

Database :
OpenAIRE
Accession number :
edsair.od.......109..e6d0d9398b685e81b23717af99c3cc95