The RAS-Regulated RAF-MEK1/2-ERK1/2 Protein Kinase Pathway: The Path Most Traveled in RASopathies

The RASopathies represent a group of developmental syndromes caused by pathogenic germline mutations in genes encoding components of the RAS-regulated RAF-MEK1/2-ERK1/2 signaling pathway as distinct from other RAS effector pathways. Individuals with RASopathy syndromes have developmental abnormalities and are predisposed to benign or malignant neoplasia, consistent with mutations in RAS, RAF, and MEK being drivers of human cancer. Cancer drug discovery efforts have seen the approval of several inhibitors of RAF, MEK1/2, and some of these are now being tested in RASopathies. Indeed, the MEK inhibitor (MEKi) selumetinib is approved for the treatment of pediatric neurofibromatosis, a RASopathy driven by mutations in NF1, which encodes a negative regulator of RAS. Given its pre-eminent role in the development of RASopathies, a thorough understanding of the ERK1/2 pathway is critical to developing clinical management strategies. Here, we introduce the key features of the RAS-regulated RAF-MEK1/2-ERK1/2 pathway, providing context for other chapters in this series. We describe the key steps in RAS activation, ERK1/2 pathway activation, and RAS inactivation, providing examples of how RASopathy mutations deregulate this key cell fate signaling pathway. We also describe the role of this pathway in cell fate decisions and its regulation, including the critical role of feedback control and therapeutic opportunities.