Effects of ERK1/2 Signaling on Cell Cycle Regulation by the Tuberin-Cyclin B1 Complex

Abstract

How cells balance growth (cell size) and division (cell number) requires a complex interplay between response to external signals including growth factors, nutrient availability and metabolic cues, along with regulation of the cell cycle. The protein Tuberin (gene TSC2) is a critical regulator of these decisions. In a complex with the protein Hamartin, Tuberin functions as a negative regulator of the Target of Rapamycin (mTOR) pathway, preventing excessive growth under unfavorable conditions. However, how this growth pathway connects to decisions to progress through the G2 phase of the cell cycle and permit cell division is still unclear. In this study, we show that post-translational modification of Tuberin by the Extracellular Signal-Regulated Kinase (ERK) pathway abrogates binding between Tuberin and the mitotic cyclin, Cyclin B1. This causes an increase in mitotic cells, due to an unregulated G2/M transition, increasing the proliferation rate. Our work shows a novel role of Tuberin in cell cycle regulation by growth and mitogenic factors independent of mTOR regulation.