scholarly journals Rab GTPases coordinate endocytosis

2000 ◽  
Vol 113 (2) ◽  
pp. 183-192 ◽  
Author(s):  
J. Somsel Rodman ◽  
A. Wandinger-Ness
Keyword(s):  
Protein Function ◽  
Current Knowledge ◽  
Integrated System ◽  
Rab Gtpase ◽  
Rab Proteins ◽  
Rab Gtpases ◽  
Gtpase Activity ◽  
Rab Protein ◽  
Membrane Budding ◽  
Endocytic Pathways

Endocytosis is characterized by vesicular transport along numerous pathways. Common steps in each pathway include membrane budding to form vesicles, transport to a particular destination, and ultimately docking and fusion with the target membrane. Specificity of vesicle targeting is rendered in part by associated Rab GTPases. This review summarizes current knowledge about Rab GTPase functions in the endocytic pathways and provides insight into the regulation of Rab GTPase activity and mechanisms of Rab protein function. Functional assays have identified some Rab proteins that operate on individual pathways, but Rab proteins in several pathways remain controversial or have not been identified. Control of Rab GTPase activity is exerted through multiple levels of regulation. Significant new information pertaining to Rab protein function in regulating transport has emerged. Remarkably, Rab5 GTPase links budding, cytoskeletal transport and docking/fusion activities. This paradigm will most likely be generally applicable to other Rab GTPase pathways. Together with the cross-talk between different Rab proteins and their effectors, this may provide an integrated system for the general coordination of endocytic pathways to maintain organelle homeostasis.

LRRK2 and Rab GTPases

2018 ◽  
Vol 46 (6) ◽  
pp. 1707-1712 ◽  
Author(s):  
Suzanne R. Pfeffer
Keyword(s):  
Membrane Trafficking ◽  
Protein Function ◽  
Short Review ◽  
Rab Gtpase ◽  
Rab Gtpases ◽  
Rab Protein ◽  
Complex Interactions ◽  
Preferential Binding ◽  
Bona Fide ◽  
Mutant Lrrk2

Leucine-rich repeat kinase 2 (LRRK2) is mutated in familial Parkinson's disease, and pathogenic mutations activate the kinase activity. A tour de force screen by Mann and Alessi and co-workers identified a subset of Rab GTPases as bona fide LRRK2 substrates. Rab GTPases are master regulators of membrane trafficking and this short review will summarize what we know about the connection between LRRK2 and this family of regulatory proteins. While, in most cases, Rab GTPase phosphorylation is predicted to interfere with Rab protein function, the discovery of proteins that show preferential binding to phosphorylated Rabs suggests that more complex interactions may also contribute to mutant LRRK2-mediated pathology.

scholarly journals Rab GTPases: master regulators that establish the secretory and endocytic pathways

2017 ◽  
Vol 28 (6) ◽  
pp. 712-715 ◽  
Author(s):  
Suzanne R. Pfeffer
Keyword(s):  
Membrane Trafficking ◽  
Membrane Microdomains ◽  
Rab Gtpase ◽  
Rab Proteins ◽  
Rab Gtpases ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Open Questions ◽  
Endocytic Pathways

Several of the most important discoveries in the field of membrane traffic have come from studies of Rab GTPases by Marino Zerial and Peter Novick and their colleagues. Zerial was the first to discover that Rab GTPases represent identity markers for different membrane-bound compartments, and each Rab organizes a collection of specific effectors into function-specifying membrane microdomains to carry out receptor trafficking. Novick discovered that the order (and thus polarity) of Rab GTPases along the secretory and endocytic pathways are established by their specific, cognate guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), which partner with one Rab to regulate the subsequent- and prior-acting Rabs. Such so-called Rab cascades have evolved to establish domains that contain unique Rab proteins and their cognate effectors, which drive all steps of membrane trafficking. These findings deserve much broader recognition by the biomedical research community and are highlighted here, along with open questions that require serious attention for full understanding of the molecular basis of Rab GTPase-regulated membrane trafficking in eukaryotic cells.

scholarly journals Rab GTPases in Parkinson’s disease: a primer

2021 ◽  
Author(s):  
Antonio Jesús Lara Ordóñez ◽  
Rachel Fasiczka ◽  
Yahaira Naaldijk ◽  
Sabine Hilfiker
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Membrane Trafficking ◽  
Protein Function ◽  
Current Knowledge ◽  
Rab Gtpases ◽  
Intracellular Membrane ◽  
Master Regulators ◽  
Rab Protein ◽  
Physiological Properties

Abstract Parkinson’s disease is a prominent and debilitating movement disorder characterized by the death of vulnerable neurons which share a set of structural and physiological properties. Over the recent years, increasing evidence indicates that Rab GTPases can directly as well as indirectly contribute to the cellular alterations leading to PD. Rab GTPases are master regulators of intracellular membrane trafficking events, and alterations in certain membrane trafficking steps can be particularly disruptive to vulnerable neurons. Here, we describe current knowledge on the direct links between altered Rab protein function and PD pathomechanisms.

A model for Rab GTPase localization

2005 ◽  
Vol 33 (4) ◽  
pp. 627-630 ◽  
Author(s):  
S. Pfeffer
Keyword(s):  
Steady State ◽  
Cellular Localization ◽  
Rab Gtpase ◽  
Rab Proteins ◽  
Rab Gtpases ◽  
Macromolecular Assemblies ◽  
Complex Interactions ◽  
Membrane Compartment ◽  
Membrane Bound ◽  
Distinct Membrane

The human genome encodes almost 70 Rab GTPases. These proteins are C-terminally geranylgeranylated and are localized to the surfaces of distinct membrane-bound compartments in eukaryotic cells. This mini review presents a working model for how Rabs achieve and maintain their steady-state localizations. Data from a number of laboratories suggest that Rabs participate in the generation of macromolecular assemblies that generate functional microdomains within a given membrane compartment. Our data suggest that these complex interactions are important for the cellular localization of Rab proteins at steady state.

scholarly journals Rab GTPases: Emerging Oncogenes and Tumor Suppressive Regulators for the Editing of Survival Pathways in Cancer

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 259 ◽  
Author(s):  
Priya D. Gopal Krishnan ◽  
Emily Golden ◽  
Eleanor A. Woodward ◽  
Nathan J. Pavlos ◽  
Pilar Blancafort
Keyword(s):  
Membrane Trafficking ◽  
Molecular Mechanisms ◽  
Intracellular Localization ◽  
Cellular Migration ◽  
Rab Gtpase ◽  
Rab Proteins ◽  
Rab Gtpases ◽  
Aberrant Expression ◽  
Post Translational Modifications ◽  
Survival Pathways

The Rab GTPase family of proteins are mediators of membrane trafficking, conferring identity to the cell membranes. Recently, Rab and Rab-associated factors have been recognized as major regulators of the intracellular positioning and activity of signaling pathways regulating cell growth, survival and programmed cell death or apoptosis. Membrane trafficking mediated by Rab proteins is controlled by intracellular localization of Rab proteins, Rab-membrane interactions and GTP-activation processes. Aberrant expression of Rab proteins has been reported in multiple cancers such as lung, brain and breast malignancies. Mutations in Rab-coding genes and/or post-translational modifications in their protein products disrupt the cellular vesicle trafficking network modulating tumorigenic potential, cellular migration and metastatic behavior. Conversely, Rabs also act as tumor suppressive factors inducing apoptosis and inhibiting angiogenesis. Deconstructing the signaling mechanisms modulated by Rab proteins during apoptosis could unveil underlying molecular mechanisms that may be exploited therapeutically to selectively target malignant cells.

scholarly journals Rab GTPase localization and Rab cascades in Golgi transport

2012 ◽  
Vol 40 (6) ◽  
pp. 1373-1377 ◽  
Author(s):  
Suzanne R. Pfeffer
Keyword(s):  
Effector Proteins ◽  
Membrane Microdomains ◽  
Rab Gtpase ◽  
Rab Gtpases ◽  
Nucleotide Exchange ◽  
Golgi Transport ◽  
Guanine Nucleotide Dissociation Inhibitor ◽  
Membrane Bound ◽  
Effector Binding ◽  
Endocytic Pathways

Rab GTPases are master regulators of membrane traffic. By binding to distinct sets of effector proteins, Rabs catalyse the formation of function-specifying membrane microdomains. They are delivered to membranes by a protein named GDI (guanine-nucleotide-dissociation inhibitor) and are stabilized there after nucleotide exchange by effector binding. In the present mini-review, I discuss what we know about how Rab GTPases are delivered to the correct membrane-bound compartments and how Rab GTPase cascades order Rabs within the secretory and endocytic pathways. Finally, I describe how Rab cascades may establish the distinct compartments of the Golgi complex to permit ordered processing, sorting and secretion of secretory cargoes.

scholarly journals Dual Prenylation Is Required for Rab Protein Localization and Function

2003 ◽  
Vol 14 (5) ◽  
pp. 1852-1867 ◽  
Author(s):  
Monica Calero ◽  
Catherine Z. Chen ◽  
Wenyan Zhu ◽  
Nena Winand ◽  
Karyn A. Havas ◽  
...  
Keyword(s):  
Protein Localization ◽  
Sole Source ◽  
Small Gtpase ◽  
Rab Proteins ◽  
Rab Gtpases ◽  
Rab Protein ◽  
Correct Function ◽  
Stable Association ◽  
And Function ◽  
Organelle Membrane

The majority of Rab proteins are posttranslationally modified with two geranylgeranyl lipid moieties that enable their stable association with membranes. In this study, we present evidence to demonstrate that there is a specific lipid requirement for Rab protein localization and function. Substitution of different prenyl anchors on Rab GTPases does not lead to correct function. In the case of YPT1 and SEC4, two essential Rab genes in Saccharomyces cerevisiae, alternative lipid tails cannot support life when present as the sole source of YPT1 and SEC4. Furthermore, our data suggest that double geranyl-geranyl groups are required for Rab proteins to correctly localize to their characteristic organelle membrane. We have identified a factor, Yip1p that specifically binds the di-geranylgeranylated Rab and does not interact with mono-prenylated Rab proteins. This is the first demonstration that the double prenylation modification of Rab proteins is an important feature in the function of this small GTPase family and adds specific prenylation to the already known determinants of Rab localization.

scholarly journals Rab8 Regulates the Actin-based Movement of Melanosomes

2005 ◽  
Vol 16 (4) ◽  
pp. 1640-1650 ◽  
Author(s):  
Marion L. Chabrillat ◽  
Claire Wilhelm ◽  
Christina Wasmeier ◽  
Elena V. Sviderskaya ◽  
Daniel Louvard ◽  
...  
Keyword(s):  
Rab Proteins ◽  
Rab Gtpases ◽  
Wild Type ◽  
In Vitro Motility Assay ◽  
Actin Bundles ◽  
In Vitro Motility ◽  
Rab Protein

Rab GTPases have been implicated in the regulation of specific microtubule- and actin-based motor proteins. We devised an in vitro motility assay reconstituting the movement of melanosomes on actin bundles in the presence of ATP to investigate the role of Rab proteins in the actin-dependent movement of melanosomes. Using this assay, we confirmed that Rab27 is required for the actin-dependent movement of melanosomes, and we showed that a second Rab protein, Rab8, also regulates this movement. Rab8 was partially associated with mature melanosomes. Expression of Rab8Q67L perturbed the cellular distribution and increased the frequency of microtubule-independent movement of melanosomes in vivo. Furthermore, anti-Rab8 antibodies decreased the number of melanosomes moving in vitro on actin bundles, whereas melanosomes isolated from cells expressing Rab8Q67L exhibited 70% more movements than wild-type melanosomes. Together, our observations suggest that Rab8 is involved in regulating the actin-dependent movement of melanosomes.

Regulation of RabGAPs involved in insulin action

2018 ◽  
Vol 46 (3) ◽  
pp. 683-690 ◽  
Author(s):  
Samaneh Mafakheri ◽  
Alexandra Chadt ◽  
Hadi Al-Hasani
Keyword(s):  
Insulin Action ◽  
Glucose Transporter ◽  
Rab Gtpase ◽  
Rab Proteins ◽  
Rab Gtpases ◽  
Gtp Hydrolysis ◽  
Gtpase Activating Proteins ◽  
Glucose Transporter Glut4 ◽  
Related Proteins

Rab (Ras-related proteins in brain) GTPases are key proteins responsible for a multiplicity of cellular trafficking processes. Belonging to the family of monomeric GTPases, they are regulated by cycling between their active GTP-bound and inactive GDP-bound conformations. Despite possessing a slow intrinsic GTP hydrolysis activity, Rab proteins rely on RabGAPs (Rab GTPase-activating proteins) that catalyze GTP hydrolysis and consequently inactivate the respective Rab GTPases. Two related RabGAPs, TBC1D1 and TBC1D4 (=AS160) have been described to be associated with obesity-related traits and type 2 diabetes in both mice and humans. Inactivating mutations of TBC1D1 and TBC1D4 lead to substantial changes in trafficking and subcellular distribution of the insulin-responsive glucose transporter GLUT4, and to subsequent alterations in energy substrate metabolism. The activity of the RabGAPs is controlled through complex phosphorylation events mediated by protein kinases including AKT and AMPK, and by putative regulatory interaction partners. However, the dynamics and downstream events following phosphorylation are not well understood. This review focuses on the specific role and regulation of TBC1D1 and TBC1D4 in insulin action.

scholarly journals Systematic proteomic analysis of LRRK2-mediated Rab GTPase phosphorylation establishes a connection to ciliogenesis

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Martin Steger ◽  
Federico Diez ◽  
Herschel S Dhekne ◽  
Pawel Lis ◽  
Raja S Nirujogi ◽  
...  
Keyword(s):  
Primary Cilia ◽  
Protein Transport ◽  
Serum Starvation ◽  
Rab Gtpase ◽  
Rab Gtpases ◽  
Rab Protein ◽  
Affinity Enrichment ◽  
Fold Reduction ◽  
Cilia Formation ◽  
Conserved Residue

We previously reported that Parkinson’s disease (PD) kinase LRRK2 phosphorylates a subset of Rab GTPases on a conserved residue in their switch-II domains (Steger et al., 2016) (PMID: 26824392). Here, we systematically analyzed the Rab protein family and found 14 of them (Rab3A/B/C/D, Rab5A/B/C, Rab8A/B, Rab10, Rab12, Rab29, Rab35 and Rab43) to be specifically phosphorylated by LRRK2, with evidence for endogenous phosphorylation for ten of them (Rab3A/B/C/D, Rab8A/B, Rab10, Rab12, Rab35 and Rab43). Affinity enrichment mass spectrometry revealed that the primary ciliogenesis regulator, RILPL1 specifically interacts with the LRRK2-phosphorylated forms of Rab8A and Rab10, whereas RILPL2 binds to phosphorylated Rab8A, Rab10, and Rab12. Induction of primary cilia formation by serum starvation led to a two-fold reduction in ciliogenesis in fibroblasts derived from pathogenic LRRK2-R1441G knock-in mice. These results implicate LRRK2 in primary ciliogenesis and suggest that Rab-mediated protein transport and/or signaling defects at cilia may contribute to LRRK2-dependent pathologies.

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