Abstract
Cdc42 is a member of the Rho family of small GTPases and a key regulator of the actin cytoskeleton, controlling cell motility, polarity and cell cycle progression. It signals downstream of the master regulator Ras and is essential for cell transformation by this potent oncogene. Overexpression of Cdc42 is observed in several cancers, where it is linked to poor prognosis. As a regulator of both cell architecture and motility, deregulation of Cdc42 is also linked to tumour metastasis. Like Ras, Cdc42 and other components of the signalling pathways it controls represent important potential targets for cancer therapeutics. In this review, we consider the progress that has been made targeting Cdc42, its regulators and effectors, including new modalities and new approaches to inhibition. Strategies under consideration include inhibition of lipid modification, modulation of Cdc42–GEF, Cdc42–GDI and Cdc42-effector interactions, and direct inhibition of downstream effectors.
Highlights
The human Ras superfamily consists of 167 members which subdivide into five families of small GTPases, with conserved structures and highly related regulatory mechanisms
In the resting state Rho family GTPases are guanine nucleotide diphosphate (GDP)-bound but nucleotide exchange facilitates binding of guanine nucleotide triphosphate (GTP), resulting in conformational changes that allow the GTPase to interact with its immediate downstream effector proteins, triggering signalling cascades
Rho family GTPases are regulated by the RhoGDI proteins, which have a number of regulatory roles
Summary
Cdc is a member of the Rho family of small GTPases and a key regulator of the actin cytoskeleton, controlling cell motility, polarity and cell cycle progression. It signals downstream of the master regulator Ras and is essential for cell transformation by this potent oncogene. Overexpression of Cdc is observed in several cancers, where it is linked to poor prognosis. Like Ras, Cdc and other components of the signalling pathways it controls represent important potential targets for cancer therapeutics. We consider the progress that has been made targeting Cdc, its regulators and effectors, including new modalities and new approaches to inhibition.
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