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Rab GTPases constitute the largest family of small GTPases (nearly 70 members in humans) and are known as main regulators of intracellular membrane traffic. Distinct Rab GTPases localize to different membrane compartments to control the specificity and directionality of membrane trafficking pathways, largely related to vesicular transport. In doing this, they contribute to conferring membrane identity and ensuring that membrane-bound cargoes are transported to their correct destinations within the cell. For a number of human Rab GTPases, several isoforms exist that perform partially redundant functions, either by working in slightly different methods or by being expressed differentially in different cell types.
Autophagy, phagocytosis, and pinocytosis are specialized endocytic cellular processes regulated by multiple Rab GTPases (Figure 1). Phagocytosis and pinocytosis are important for the uptake of small particles and bacterial pathogens by cells of the immune system, while autophagy is a ubiquitous housekeeping function vital for the autodigestion of cell constituents and pathogen clearance. Overlapping GTPase subsets work in concert to regulate macropinosome, phagosome, and autophagosome formation. For instance, degradative enzyme delivery to phagosomes and autophagosomes occurs through a common mechanism involving fusion with endo/lysosomes and is regulated by Rab7. Whether it is autophagy, endocytosis or phagocytosis, the roles of Rab GTPase are tightly regulated by interactions with partner proteins that ensure the integrity of these vital processes.
Figure 1. Rab GTPases in endocytosis, recycling, and degradative pathways.
Given the importance of Rab GTPases in membrane traffic, and the importance of membrane traffic for human health, it is perhaps surprising that only a limited number of genetic diseases are associated with Rab dysfunctions. The existence of multiple Rab isoforms and trafficking pathways presumptively makes humans less vulnerable to mutations in individual Rab-encoding genes. However, several mutations in Rab GTPases or their effectors or regulators are associated with genetic diseases. Examples of genetic diseases associated with mutations in Rab GTPases include immunodeficiencies, albinism, neuropathies, mental retardation and ciliopathies.
Rab GTPase pathways can interface hierarchically with other GTPases to integrate cell signaling and trafficking. Moreover, dysregulated or mutant Rab GTPases and accessory proteins underlie many acquired and genetic human diseases. Foundational studies indicate that GTPases can be targeted by altering nucleotide binding or regulatory protein interactions with small molecules. Questions still remain as to how tissue-specific pathologies arise from mutant GTPases that are omnipresent and expressed in all cells. This could be due to redundant pathways or GTPase functions in some cell types, as well as tissue-specific effectors or regulators. Thus, GTPase-targeted interventions and therapeutics, greater clarity in this arena will be essential. It will also be important to couple GTPase interventions with appropriate tissue-targeting strategies.
Creative Biogene is able to offer a variety of Rab GTPase pathway related products including stable cell lines, viral particles and clones for your drug discovery projects.
Rab GTPase Pathway Product Panel
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