Targeting RAS-ERK pathway an insight into scaffold proteins in thyroid cancer

Abstract

An overwhelming body of data unquestionably links the Ras-ERK signaling pathway to cellular transformation and to the upbringing of human malignancies. Once this cascade is activated, the MAP Kinases phosphorylate and control the activity of key cytoplasmic molecules and nuclear proteins, which can regulate gene expression and participate in processes as important as proliferation, differentiation and cell survival. 70% of thyroid carcinomas have activating mutations in some of the components of this route, specifically Ras (20%) and BRaf (40%), so the inhibition of aberrant signaling through this cascade may be a valid therapeutic strategy for this type of tumors. Scaffold proteins optimize Ras-ERK signals and modulate their intensity and spatial fidelity, acting as dimerization platforms. As such they could decisively intervene in signals conveyed through the RAS-ERK pathway to evoke thyroid tumors. We have used cellular models representative of different oncogenic driver lesions, namely BRaf, H/K/NRas and Ret/PTC, to study the role of scaffold proteins in thyroid tumorigenesis, in order to identify those scaffold essentials for the maintenance of the oncogenic phenotype. In addition, we have also investigated how either up- or downregulation of defined scaffold proteins affects the response of thyroid tumor cells to classical RAS-ERK pathway inhibitors depending on the driver lession.