Scaffold proteins and cytoskeletal dynamics as modulators of Ras-ERK pathway in cancer

Abstract

An overwhelming body of data unquestionably links the Ras-ERK pathway to the upbringing and progression of human malignancies. About 40% of human cancers harbor activating mutations in proteins involved in this signaling cascade, in particular Ras and Braf. In addition to the main proteins of this signaling pathway, there are several regulatory proteins known as scaffold proteins, that modulate the intensity, amplitude and duration of ERK signals. Interestingly, it can propose the scaffold proteins as antitumoral targets. Considering the hypothesis that scaffold proteins interact and regulate the signal transduction through the Ras-ERK pathway in a coordinated manner we try to find out how these interactions are regulated. Ras proteins are distributed in different types of plasma membrane: microdomains and endomembranes. We have previously demonstrated that compartmentalization dictates Ras utilization of effectors, the intensity of its signals and the biological response of the cells. Cell migration is critical for many physiological processes and is often misregulated in developmental disorders and pathological conditions including cancer. MAPK signaling are known regulators of cytoskeletal dynamics during cellular processes such as cell adhesion and migration. Our hypothesis is that localized ERK signaling mediated through recently identified scaffold proteins and its interactions with the cytoskeleton may regulate specific cellular responses. Here we propose that associations among different scaffold proteins and cytoskeleton will add one further degree of regulation for an already tightly regulated cascade and could provide a novel means for manipulating ERK signals, even with therapeutic purposes.