The contribution of RAS function to transformation of the colonic epithelium: functional differences, similarities, and cooperation between RAS family members

Abstract

Constitutively activating mutations of members of the RAS family of small G proteins provide an important oncogenic contribution to a significant percentage of human cancers. Despite nearly 25 years of investigation, important questions about the function of these proteins and their relationships to one another remain unresolved. We have undertaken a series of studies to address some of these questions and herein report novel findings regarding the relationship of these family members to one another and their respective contributions to the progression of human disease. Briefly, we examine the uniquely potent oncogenic contribution of K-RAS to cell lines derived from human tumors and identify some previously unappreciated findings regarding the mechanisms by which this protein promotes tumorigenesis. Interestingly, we present data to support that K-RAS requires the activity of another family member, NRAS to realize its full oncogenic potential in certain contexts, and that represents the first biochemical evidence of a relationship between RAS family members. We additionally challenge earlier notions about effector pathways long thought to be essential for RAS-driven transformation, as well as disprove an accepted and widespread assay for measuring the activity of RAS proteins.