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Regulators and Effectors of ras Proteins
Published in Juan Carlos Lacal, Frank McCormick, The ras Superfamily of GTPases, 2017
If inhibiting exchange activity reduces ras-p21 signaling, we might expect that increasing exchange activity would increase ras-p21 function. This has been demonstrated recently by Takai and co-workers, who have overexpressed RHO-GDS in mammalian cells, and found that this protein, which increases the rate of GDP dissociation from K-ras p21, causes oncogenic transformation.13 Increased exchange can also be achieved by using mutant forms of ras-p21 that have high intrinsic dissociation rates for GDP. Such mutants have been described, and shown to be oncogenic.27 It is, therefore, clear that the level of ras activation in cells can be altered by increasing or decreasing exchange factor activity: whether this is a mechanism by which ras proteins are normally regulated remains to be demonstrated directly. In addition, proteins may exist that regulate the rate of dissociation of GDP from ras proteins. Guanine nucleotide dissociation inhibitors (GDIs) for ras-related proteins have been identified18,26 and cloned,8,14 but to date no such GDI for ras-p21 has been identified.
Rho-kinase inhibitors: Role in corneal endothelial disorders
Published in Seminars in Ophthalmology, 2023
Nimish Kumar Singh, Srikant Kumar Sahu
Rho-kinase is a Serine/Threonine protein kinase that regulates cellular shape and adhesion through its action on the cytoskeleton.1 It exerts its effect on Rho-A protein which plays a major role in the functioning of the cytoskeletal machinery, by facilitating its transformation between an active conformation bound to Guanosine Triphosphate (GTP) and an inactive one bound to Guanosine Diphosphate (GDP). Various other factors such as Guanine nucleotide Exchange Factors (GEFs), GTPase Activating Proteins (GAPs), and Guanine nucleotide Dissociation Inhibitors (GDIs) also play a major role in this activation along with Rho-kinase. Through these interactions, Rho-A protein makes a significant contribution toward cellular adhesion and proliferation and determines the morphological changes in cells via its effect on the actin and myosin contractility.2 Rho- A and its effector Rho-kinase 2 (ROCK 2) are predominantly expressed in human corneal endothelial cells, thereby mediating the actomyosin contraction of endothelial cells as well.