mTORC1 regulates cytokinesis through activation of Rho-ROCK signaling

TL;DR

This study uncovers a novel pathway where mTORC1 promotes cytokinesis by activating Rho-ROCK signaling, linking cell size regulation with cell division processes and revealing potential targets for controlling cell proliferation.

Contribution

It demonstrates that mTORC1 hyperactivation causes cytokinesis defects via Rho-ROCK pathway activation, a novel connection between mTOR signaling and cell division.

Findings

mTORC1 hyperactivation induces polyploidy and cytokinesis failure.

Inhibition of mTORC1 or ROCK rescues cytokinesis defects.

mTORC1 promotes Rho-GTP loading and actin-myosin contractility during cytokinesis.

Abstract

Understanding the mechanisms by which cells coordinate their size with their ability to divide has long attracted the interest of biologists. The Target of Rapamycin (TOR) pathway is becoming increasingly recognized as a master regulator of cell size, however less is known how TOR activity might be coupled with the cell cycle. Here, we establish that mTOR complex 1 (mTORC1) promotes cytokinesis through activation of a Rho GTPase-Rho Kinase (ROCK) signaling cascade. Hyperactivation of mTORC1 signaling by depletion of any of its negative regulators: TSC1, TSC2, PTEN, or DEPTOR, induces polyploidy in a rapamycin-sensitive manner. mTORC1 hyperactivation-mediated polyploidization occurs by a prolonged, but ultimately failed attempt at abcission followed by re-fusion. Similar to the effects of ROCK2 overexpression, these mTORC1-driven aberrant cytokinesis events are accompanied by increased Rho-GTP loading, extensive plasma membrane blebbing, and increased actin-myosin contractility, all of which can be rescued by either mTORC1 or ROCK inhibition. These results provide evidence for the existence of a novel mTORC1-Rho-ROCK pathway during cytokinesis and suggest that mTORC1 might play a critical role in setting the size at which a mammalian cell divides.