The Noncanonical RAS/MAPK Pathway and the RASopathies

RASopathies are neurodevelopmental genetic disorders caused by germline variants in genes that encode critical components and/or regulators of the RAS/Mitogen-activated protein kinase (MAPK) pathway. These syndromes are characterized by overlapping clinical features, including congenital cardiac defects, distinctive facial features, cognitive impairment, and predisposition to cancer, among others. Decades of research into the function and regulation of the RAS/MAPK pathway have led to our current understanding of this critical signaling pathway. Through extensive scientific evidence, it has been possible to define the main components of the RAS/MAPK signaling and begin to draw a model for the so-called canonical RAS/MAPK pathway. This modular signaling core, nucleated by the RAS GTPases N, H, and KRAS, is triggered by extracellular cues and propagates downstream signaling through a MAPK signaling cascade formed by the kinases RAF/MEK/ERK. In addition to this canonical signaling, many studies have demonstrated that this pathway is regulated by other proteins and alternative mechanisms, highlighting the complexity and the context-specific function of RAS/MAPK pathway. Importantly, variants in the genes encoding these less-understood proteins have also been identified in different types of RASopathies. In this chapter, we discuss the role of this noncanonical RAS/MAPK pathway and its importance in the context of these disorders.