Research Summary

Modulation of physiological and oncogenic Ras protein signaling via plasma membrane clustering

Activated KRas signaling is among the most common molecular drivers in human cancers, but therapeutic targeting of KRas remains a challenge. Emerging evidence suggests that the dynamics of KRas proteins in cellular membranes, in particular, their homo- and hetero-typic interactions in nanoscale protein clusters in these membranes, drives KRas-mediated signaling. The central aim here is to elucidate the mechanisms that underlie KRas protein clustering in the plasma membrane, and its role in physiological and oncogenic signaling.

The second objective is to investigate the role of cortical actin embedded beneath the cytoplasmic side plasma membrane in regulating the nanocluster architecture of Ras proteins. I hypothesize that the protein and lipid sorting by cortical cytoskeletal filaments create restrictive environment for the plasma membrane associated KRas protein diffusion and hence imparting a definite nanocluster architecture. This nanoscale organization of Ras proteins is essential for its signaling activity. This mechanistic control via cortical actin serves an internal feedback control mechanism to maintain high fidelity signaling at the plasma membrane especially in case of oncogenic KRas, which is uncoupled to receptor-initiated signals.