Drosophila miR-33-5p Suppresses Cell Growth by Inhibiting ERK Signaling

Cell growth control is a critical process underlying diverse biological events, including survival, development, tissue repair, and disease. Growth regulation is orchestrated by a combination of external and internal cues, involving a multitude of signaling pathways. Nevertheless, our comprehension of the regulation of growth-associated signaling pathways is still incomplete. In this study, we discovered that microRNA miR-33 overexpression in Drosophila S2 cells resulted in a reduction in cell proliferation. This growth inhibition was attributed to the inactivation of ERK signaling, which is mediated through Ras64B, a direct target of miR-33-5p. In accordance with these observations in S2 cells, miR-33 inactivation in Drosophila wings led to an increase in cell number, while its overexpression resulted in a decrease. Notably, miR-33-induced wing reduction was associated with diminished ERK signaling, and this wing defect was rescued by co-expression of Ras64B or a constitutively active ERK variant. Consequently, these findings establish miR-33–Ras64B–ERK as a regulatory axis, providing new mechanistic insights into growth control in Drosophila.