Abstract
Rho GTPases are members of the Ras superfamily of GTPases that regulate a wide variety of cellular functions. While Rho GTPase pathways have been implicated in various pathological conditions in humans, to date coding mutations in only the hematopoietic specific GTPase,RAC2, have been found to cause a human disease, a severe phagocytic immunodeficiency characterized by life-threatening infections in infancy. Interestingly, the phenotype was predicted by a mouse knock-out ofRAC2and resembles leukocyte adhesion deficiency (LAD). Here we review Rho GTPases with a specific focus on Rac GTPases. In particular, we discuss a new understanding of the unique and overlapping roles of Rac2 in blood cells that has developed since the generation of mice deficient in Rac1, Rac2 and Rac3 proteins. We propose that Rac2 mutations leading to disease be termed LAD type IV.
Highlights
Rho GTPasesThe Rho family of GTPases are genes that encode small monomeric Ras-related proteins [9]
Rho GTPases are members of the Ras superfamily of GTPases that regulate a wide variety of cellular functions
Rac GTPases are important in maintaining red blood cell membrane integrity [47] and appear to be critical for enucleation [46]; Rac1∆/∆; Rac2−/− mice develop microcytic anemia with a hemoglobin drop of about 20% and significant anisocytosis and poikilocytosis associated with reticulocytosis suggestive of a hemolytic process
Summary
The Rho family of GTPases are genes that encode small monomeric Ras-related proteins [9]. Similar to Ras proteins, Rho GTPases are subject to posttranslational modifications, in which the proteins are lipid modified by prenylation at a conserved cysteine in the carboxy(C)-terminal CaaL sequence (where C is cysteine, a is an aliphatic amino acid, and L is leucine). Adjacent to this CaaL sequence, several members of the family contain an important ‘polybasic domain’, which has been shown in Ras proteins to modify the strength of the membrane localization. Lipid modifications of Rho GTPases are critical for membrane association and for protein-protein interactions [64] As described below, both the ‘polybasic’ domain and the conserved CaaL sequence are important in determining Rac protein localization and function in blood cells. This review will focus on Rho GTPases of the Rac family, and the role of RAC2 in human diseases
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