The impact of RAS on cell differentiation in health and disease

RAS proteins have been studied for more than 40 years, mainly in the context of cancer. Given that RAS signaling promotes cell cycle progression, it is commonly assumed that its main function is to drive cell proliferation. In this review, we will, however, address the roles of RAS during cell differentiation, which is intertwined with cell division during organismal development and tissue homeostasis in the adult. Our analysis suggests a far-reaching and profound impact of RAS signaling in associated processes. During vertebrate embryonal development, the FGF-RAS-ERK signaling axis is involved as early as germ layer induction and embryonal patterning. Current evidence suggests that RAS fundamentally controls the balance between stem cells and their differentiated progeny. RAS signaling needs to be downmodulated to sustain pluripotent stem cells. Inhibition of RAS activity is also required to preserve adult stem cell quiescence. At the other end of the differentiation spectrum, a different kind of RAS inactivation by the GTPase-activating protein (GAP) neurofibromin 1 (NF1) appears central to permit terminal differentiation, e.g., of muscle tissue. This latter process is disabled in muscle-borne cancer and likely also in other cancer types. In the RAS-associated developmental diseases, the RASopathies, cell differentiation appears to be broadly perturbed throughout development. We suggest that loss of RAS pathway activity mainly manifests in the stem/progenitor cell compartment, whereas inhibition of NF1 GAP-mediated RAS inactivation blocks terminal differentiation. Given that defects accumulate during development, it is plausible to assume that only progressive pathological phenotypes of RASopathies offer a realistic chance for treatment, notably by repurposing RAS-MAPK pathway oncology drugs. Thus, the impact of RAS on cell differentiation represents, in our view, the common mechanistic denominator of cancer and RASopathies. We conclude by giving a perspective on how improving our insight into the functioning of RAS during cell differentiation could lead to the development of misdifferentiation-correcting drugs.