Mechanosignaling

What are Rab GTPases?

The Rab proteins constitute the largest family of small GTPases belonging to the Ras superfamily, with approximately 70 members identified in humans. Rab GTPases are the primary regulators of the vesicular trafficking pathways that are responsible for transporting the vast array of cellular cargo across membrane organelles. The Rabs function as molecular switches in regulating the formation, transport, docking, and fusion of transport vesicles during membrane transport [1][2].

Rab Regulators and Effectors

The subcellular localization and activity of the Rab proteins depend on their nucleotide-bound states and the cycling between activated, membrane-linked Rab-GTP and inactive cytosolic Rab-GDP is regulated by a group of GEFs, GAPs and GDIs. Membrane anchorage occurs via geranylgeranyl groups on the cytoplasmic domain of the Rabs and is facilitated by Rab Escort Proteins (REPs), which present the newly synthesized Rabs to geranyl transferases for prenylation. The membrane specificity for the different Rabs is provided by GDI Displacement Factors (GDFs) that identify distinct Rab-GDI complexes from the cytosol and promote the dissociation of the GDIs, before delivering the Rabs to the membrane [3]. Activated Rabs function by recruiting a distinct set of effectors such as coat proteins [4], cytoskeletal motors [5][6], kinases and phosphatases [7] and membrane fusion proteins [8][9] for mediating the various pathways of membrane transport. Disrupted trafficking resulting from dysfunction of the Rab GTPases, their regulators or effectors is associated with tumorigenesis [10], viral and bacterial infections [11][12] and several inherited disorders of the nervous system, eyes, skin, and bones [13][14][15].

Rab GTPase functions

Cellular communication with the extracellular environment is mediated by the inward and outward trafficking of vesicles during endocytic and exocytic/secretory pathways, as seen in physiological processes such as immune responses, embryonic morphogenesis and endocrine signaling. The directionality and specificity of cargo transport amidst intricately connected pathways is maintained by the association of specific Rabs with distinct intracellular membranes and their transport vesicles.

Rab GTPases in endocytosis and exocytosis pathways

Rab GTPases in endocytic pathways

Some of the Rab isoforms commonly identified in the endocytic pathway are Rab4, Rab5, Rab7 and Rab11; Rab4, Rab5 and Rab11 function in the early endocytic pathway, whereas Rab7 and Rab9 regulate the later stages of endocytosis (reviewed in [16]). Rab5 primes the pathway by regulating the formation of coated vesicles, the fusion of vesicles with early endosomes and the homophilic fusion between early endosomes [17]. Endosomal maturation into multivesicular bodies, followed by fusion to lysosomes is controlled by Rab7 GTPase [18], though later studies have suggested a dispensable role for Rab7 in endosomal maturation [19]. Recent work has also associated the Rab7b isoform with later stages of trafficking to the trans-golgi network [20]. Rab4, Rab 11 and Rab9 are the recycling GTPases and mediate retro-transport of the cargo to the plasma membrane and the Golgi complex [21][22]. Rab11-mediated endosomal recycling is shown to be essential for the maintenance of cellular polarity [23].

Rab GTPases in exocytic/secretory pathways

In the presence of external stimuli, the exocytosis of secretory products stored in cell-specific organelles is regulated by Rab GTPases such as Rab3 and Rab27. The localization of Rab27 on secretory lysosomes such as melanosomes in melanocytes, lytic granules in cytotoxic T cells and dense granules in platelets is directly linked to its regulation of melanosome transport and lytic granule exocytosis [24]. In humans, mutations resulting in a loss-of-function in Rab27 is associated with Gricelli syndrome, characterized by partial cutaneous albinism and immunodeficient phenotypes [25][26]. Rab27 is also known to regulate the exocytosis of conventional secretory granules in various endocrine, exocrine and immune cells [27]. The Rab3 isoforms have been identified as regulators of the terminal stages of exocytosis in brain and endocrine cells. In brain cells, Rab3 regulates the late stages of synaptic vesicle fusion and neurotransmitter release [28], while in endocrine cells such as the pancreatic beta cells, Rab3 associates with the secretory granules and facilitates their rapid replenishment into releasable vesicle pools [29].

Rab GTPase in actin remodeling

Outside their canonical role in membrane trafficking, the Rabs function in various cellular processes such as proliferation, adhesion, motility and survival. Rab7b has been specifically associated with RhoA activation and myosin light chain phosphorylation, thereby facilitating cell polarization, adhesion and migration [30]. Recent studies have proposed a role for the early endosome regulator, Rab5, in cell migration that involves Rho GTPase-mediated integrin signaling and focal adhesion disassembly [31].

References

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