Rho Proteins in Cancer
From the earliest stages of embryonic development through the metastatic spread of cancer cells, cell motility is a critical feature of life. The Ras homology, or Rho, family of small GTPases plays a broad and essential role in all stages of cell motility. Rac and Cdc42 remodel the actin cytoskeleton at the leading edge of the cell, resulting in membrane ruffles and protrusions, while Rho is largely responsible for orchestrating focal adhesion assembly and generating contractile forces at the rear of the cell, thus permitting cell movement across these adhesive contacts and subsequent detachment by the trailing end of the cell. Activation and inactivation of these small GTPases is modulated by a group of regulatory proteins - guanine nucleotide exchange factors (GEFs) activate, while GTPase activating proteins (GAPs) and guanine nucleotide dissociation inhibitors (GDIs) inhibit GTPase activity. Rho family proteins do not typically directly exert their effects on cell motility, but instead operate through a multitude of effector proteins, which each carry out a subset of motility-related functions. Because of their crucial roles in cell motility, Rho family protein expression and activation is altered in almost all types of cancer. As the body of knowledge surrounding Rho proteins, their interactions, and their regulation grows, so do the options for therapeutic intervention at an essential point of metastatic dissemination.
KeywordsGuanine Nucleotide Exchange Factor Pleckstrin Homology Domain CAAX Motif Focal Adhesion Assembly Actin Stress Fiber Formation
This work was supported by the Burroughs Wellcome Fund, the Breast Cancer Research Foundation, the Department of Defense Breast Cancer Research Program (BC083217 and BC083262), and the National Institutes of Health (CA-77612).
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