oa Editorial [Hot Topic: Small GTPase Signaling in Cell Physiology and Disease (Guest Editor: Crislyn D'Souza-Schorey)]

Ras-related small GTP-binding proteins (also commonly referred to as small GTPases) comprise a large group of highly conserved signaling proteins with more than 100 mammalian family members. Many of these proteins are components of signaling pathways that link extracellular signals via transmembrane receptors to cytoplasmic or nuclear responses. Based on structure, sequence and function, the Ras superfamily can be categorized into distinct families -Ras, ARF, Rho, Rab, Ran, Rheb, Rap, Rit and Rad, each of which may be further divided into subfamilies. They function as molecular switches cycling between their active, GTP-bound, and inactive, GDP-bound, conformations [1]. Named for their ability to bind and hydrolyze GTP, it is now known that the intrinsic GTPase activity of many of these molecules is low to negligible [2]. Molecules that regulate nucleotide cycling on these proteins include GTPase activating proteins (GAPs), which promote hydrolysis of bound GTP and thus favor the inactive state, and GTP exchange factors (GEFs) which facilitate the exchange of bound GDP for GTP and thereby, GTPase activation. These Ras-like signaling proteins are essential for multiple cellular processes such as cell proliferation, dynamics of the cytoskeleton, membrane trafficking, and nucleo-cytoplasmic transport. They are involved in many physiological processes, including establishment and maintenance of polarity, adhesion, migration, cell division, cell differentiation and tissue regeneration. Given their pivotal role in so many critical developmentally regulated processes, small GTPases are involved in a wide spectrum of pathological human conditions, such as tumor growth and metastasis in cancer progression, inflammation and vascular diseases, mental retardation, and infections. This mini-issue covers diverse aspects of the cell biology and the biochemical regulation the small GTP binding proteins as well as their individual and collective cell biological functions in health and disease. Specific topics addressed include the roles and regulators of Rho and Rab families of small GTPases in cancer progression, as well as how signal transduction mediated by these same proteins can impinge on neurodegenerative disease. Rheb-regulated signaling, including its potential to provide novel anti-cancer therapeutics, is also reviewed.