Abstract
Small GTPases are a family of low molecular weight GTP-hydrolyzing enzymes that cycle between an inactive state when bound to GDP and an active state when associated to GTP. Small GTPases regulate key cellular processes (e.g., cell differentiation, proliferation, and motility) as well as subcellular events (e.g., vesicle trafficking), making them key participants in a great array of pathophysiological processes. Indeed, the dysfunction and deregulation of certain small GTPases, such as the members of the Ras and Arf subfamilies, have been related with the promotion and progression of cancer. Therefore, the development of inhibitors that target dysfunctional small GTPases could represent a potential therapeutic strategy for cancer treatment. This review covers the basic biochemical mechanisms and the diverse functions of small GTPases in cancer. We also discuss the strategies and challenges of inhibiting the activity of these enzymes and delve into new approaches that offer opportunities to target them in cancer therapy.
Highlights
Small GTPases are a large family of hydrolases that bind and hydrolyze GTP to GDP in order to regulate many cellular activities [1]
Possible mechanisms by which new inhibitors can be designed include the development of molecules that prevent the formation of the specific guanine-nucleotide exchange factors (GEFs)-GTPases complex, the impairment of the binding of GTP to GTPases, the increase of GTPase-activating proteins (GAPs) protein activity to reduce the pool of active small GTPases, the blocking of the transduction of the activation signal to their specific downstream effector and the inhibition of their membrane-binding domain (Figure 2) [34,36]
We showed for the first time that active GTP-bound Arf1 is much higher in metastatic head and neck squamous cell carcinoma (HNSCC)
Summary
Small GTPases are a large family of hydrolases that bind and hydrolyze GTP to GDP in order to regulate many cellular activities (e.g., cell differentiation, proliferation, and motility) [1]. Small GTPases have a basal mild endogenous GTPase activity that is dependent on Mg2+ to weaken the bond between the last two phosphates in GTP in order to form GDP [2,3,4]. Small GTPases have been grouped into five major classes according to their sequence homology and on their physiological functions [3]: Arf subfamily, Ras subfamily, Ras-homolog (Rho) subfamily, Ras-related in brain (Rab) subfamily, and Ras-related nuclear protein (Ran) subfamily [5,6]. Adhesion kinase (FAK) [12,13,14]
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