Faculty Opinions recommendation of Who's in control? Principles of Rab GTPase activation in endolysosomal membrane trafficking and beyond.

2021 ◽  
Author(s):  
Mitsunori Fukuda
Keyword(s):  
Membrane Trafficking ◽  
Rab Gtpase ◽  
Gtpase Activation

Who’s in control? Principles of Rab GTPase activation in endolysosomal membrane trafficking and beyond

2021 ◽  
Vol 220 (9) ◽  
Author(s):  
Ann-Christin Borchers ◽  
Lars Langemeyer ◽  
Christian Ungermann
Keyword(s):  
Membrane Trafficking ◽  
Transport Processes ◽  
Rab Gtpase ◽  
Rab Gtpases ◽  
Nucleotide Exchange ◽  
Organelle Biogenesis ◽  
Nucleotide Exchange Factor ◽  
Recent Developments ◽  
Gtpase Activation

The eukaryotic endomembrane system consists of multiple interconnected organelles. Rab GTPases are organelle-specific markers that give identity to these membranes by recruiting transport and trafficking proteins. During transport processes or along organelle maturation, one Rab is replaced by another, a process termed Rab cascade, which requires at its center a Rab-specific guanine nucleotide exchange factor (GEF). The endolysosomal system serves here as a prime example for a Rab cascade. Along with endosomal maturation, the endosomal Rab5 recruits and activates the Rab7-specific GEF Mon1-Ccz1, resulting in Rab7 activation on endosomes and subsequent fusion of endosomes with lysosomes. In this review, we focus on the current idea of Mon1-Ccz1 recruitment and activation in the endolysosomal and autophagic pathway. We compare identified principles to other GTPase cascades on endomembranes, highlight the importance of regulation, and evaluate in this context the strength and relevance of recent developments in in vitro analyses to understand the underlying foundation of organelle biogenesis and maturation.

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: 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 Cell cycle–dependent phosphorylation of Sec4p controls membrane deposition during cytokinesis

2016 ◽  
Vol 214 (6) ◽  
pp. 691-703 ◽  
Author(s):  
Dante Lepore ◽  
Olya Spassibojko ◽  
Gabrielle Pinto ◽  
Ruth N. Collins
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Cell Cycle ◽  
Membrane Trafficking ◽  
Intracellular Trafficking ◽  
Rab Gtpase ◽  
Rab Gtpases ◽  
Positive Regulator ◽  
Physiological Relevance ◽  
A Cell ◽  
Cycle Dependent

Intracellular trafficking is an essential and conserved eukaryotic process. Rab GTPases are a family of proteins that regulate and provide specificity for discrete membrane trafficking steps by harnessing a nucleotide-bound cycle. Global proteomic screens have revealed many Rab GTPases as phosphoproteins, but the effects of this modification are not well understood. Using the Saccharomyces cerevisiae Rab GTPase Sec4p as a model, we have found that phosphorylation negatively regulates Sec4p function by disrupting the interaction with the exocyst complex via Sec15p. We demonstrate that phosphorylation of Sec4p is a cell cycle–dependent process associated with cytokinesis. Through a genomic kinase screen, we have also identified the polo-like kinase Cdc5p as a positive regulator of Sec4p phosphorylation. Sec4p spatially and temporally localizes with Cdc5p exclusively when Sec4p phosphorylation levels peak during the cell cycle, indicating Sec4p is a direct Cdc5p substrate. Our data suggest the physiological relevance of Sec4p phosphorylation is to facilitate the coordination of membrane-trafficking events during cytokinesis.

scholarly journals Evi5 promotes collective cell migration through its Rab-GAP activity

2012 ◽  
Vol 198 (1) ◽  
pp. 57-67 ◽  
Author(s):  
Carl Laflamme ◽  
Gloria Assaker ◽  
Damien Ramel ◽  
Jonas F. Dorn ◽  
Desmond She ◽  
...  
Keyword(s):  
Cell Migration ◽  
Membrane Trafficking ◽  
Rab Gtpase ◽  
Collective Cell Migration ◽  
Border Cells ◽  
Gtpase Activating Proteins ◽  
Guidance Receptors ◽  
Dependent Polarization ◽  
Drosophila Protein ◽  
Molecular Machinery

Membrane trafficking has well-defined roles during cell migration. However, its regulation is poorly characterized. In this paper, we describe the first screen for putative Rab–GTPase-activating proteins (GAPs) during collective cell migration of Drosophila melanogaster border cells (BCs), identify the uncharacterized Drosophila protein Evi5 as an essential membrane trafficking regulator, and describe the molecular mechanism by which Evi5 regulates BC migration. Evi5 requires its Rab-GAP activity to fulfill its functions during migration and acts as a GAP protein for Rab11. Both loss and gain of Evi5 function blocked BC migration by disrupting the Rab11-dependent polarization of active guidance receptors. Altogether, our findings deepen our understanding of the molecular machinery regulating endocytosis and subsequently cell signaling during migration.

scholarly journals Trs65p, a subunit of the Ypt1p GEF TRAPPII, interacts with the Arf1p exchange factor Gea2p to facilitate COPI-mediated vesicle traffic

2011 ◽  
Vol 22 (19) ◽  
pp. 3634-3644 ◽  
Author(s):  
Shuliang Chen ◽  
Huaqing Cai ◽  
Sei-Kyoung Park ◽  
Shekar Menon ◽  
Catherine L. Jackson ◽  
...  
Keyword(s):  
Membrane Trafficking ◽  
Rab Gtpase ◽  
Vesicle Traffic ◽  
Exchange Factor ◽  
Γ Subunit ◽  
C Terminus ◽  
A Subunit ◽  
Distinct Membrane

The TRAPP complexes are multimeric guanine exchange factors (GEFs) for the Rab GTPase Ypt1p. The three complexes (TRAPPI, TRAPPII, and TRAPPIII) share a core of common subunits required for GEF activity, as well as unique subunits (Trs130p, Trs120p, Trs85p, and Trs65p) that redirect the GEF from the endoplasmic reticulum–Golgi pathway to different cellular locations where TRAPP mediates distinct membrane trafficking events. Roles for three of the four unique TRAPP subunits have been described before; however, the role of the TRAPPII-specific subunit Trs65p has remained elusive. Here we demonstrate that Trs65p directly binds to the C-terminus of the Arf1p exchange factor Gea2p and provide in vivo evidence that this interaction is physiologically relevant. Gea2p and TRAPPII also bind to the yeast orthologue of the γ subunit of the COPI coat complex (Sec21p), a known Arf1p effector. These and previous findings reveal that TRAPPII is part of an Arf1p GEF-effector loop that appears to play a role in recruiting or stabilizing TRAPPII to membranes. In support of this proposal, we show that TRAPPII is more soluble in an arf1Δ mutant.

scholarly journals Regulation of exosome secretion by Rab35 and its GTPase-activating proteins TBC1D10A–C

2010 ◽  
Vol 189 (2) ◽  
pp. 223-232 ◽  
Author(s):  
Chieh Hsu ◽  
Yuichi Morohashi ◽  
Shin-ichiro Yoshimura ◽  
Natalia Manrique-Hoyos ◽  
SangYong Jung ◽  
...  
Keyword(s):  
Membrane Trafficking ◽  
Rab Gtpase ◽  
Multivesicular Bodies ◽  
Dependent Manner ◽  
Intracellular Accumulation ◽  
Gtpase Activating Proteins ◽  
The Central Nervous System ◽  
And Function ◽  
Endosomal Vesicles ◽  
Activity Dependent

Oligodendrocytes secrete vesicles into the extracellular space, where they might play a role in neuron–glia communication. These exosomes are small vesicles with a diameter of 50–100 nm that are formed within multivesicular bodies and are released after fusion with the plasma membrane. The intracellular pathways that generate exosomes are poorly defined. Because Rab family guanosine triphosphatases (GTPases) together with their regulators are important membrane trafficking organizers, we investigated which Rab GTPase-activating proteins interfere with exosome release. We find that TBC1D10A–C regulate exosome secretion in a catalytic activity–dependent manner. We show that Rab35 is the target of TBC1D10A–C and that the inhibition of Rab35 function leads to intracellular accumulation of endosomal vesicles and impairs exosome secretion. Rab35 localizes to the surface of oligodendroglia in a GTP-dependent manner, where it increases the density of vesicles, suggesting a function in docking or tethering. These findings provide a basis for understanding the biogenesis and function of exosomes in the central nervous system.

scholarly journals Large-Scale Profiling of Rab GTPase Trafficking Networks: The Membrome

2005 ◽  
Vol 16 (8) ◽  
pp. 3847-3864 ◽  
Author(s):  
Cemal Gurkan ◽  
Hilmar Lapp ◽  
Christelle Alory ◽  
Andrew I. Su ◽  
John B. Hogenesch ◽  
...  
Keyword(s):  
Membrane Trafficking ◽  
Large Scale ◽  
Building Blocks ◽  
Rab Gtpase ◽  
Rab Gtpases ◽  
Coding System ◽  
Clustering Methods ◽  
Protein Activity ◽  
Organ Systems ◽  
Hierarchical Clustering Methods

Rab GTPases and SNARE fusion proteins direct cargo trafficking through the exocytic and endocytic pathways of eukaryotic cells. We have used steady state mRNA expression profiling and computational hierarchical clustering methods to generate a global overview of the distribution of Rabs, SNAREs, and coat machinery components, as well as their respective adaptors, effectors, and regulators in 79 human and 61 mouse nonredundant tissues. We now show that this systems biology approach can be used to define building blocks for membrane trafficking based on Rab-centric protein activity hubs. These Rab-regulated hubs provide a framework for an integrated coding system, the membrome network, which regulates the dynamics of the specialized membrane architecture of differentiated cells. The distribution of Rab-regulated hubs illustrates a number of facets that guides the overall organization of subcellular compartments of cells and tissues through the activity of dynamic protein interaction networks. An interactive website for exploring datasets comprising components of the Rab-regulated hubs that define the membrome of different cell and organ systems in both human and mouse is available at http://www.membrome.org/ .

scholarly journals Rab1b overexpression modifies Golgi size and gene expression in HeLa cells and modulates the thyrotrophin response in thyroid cells in culture

2013 ◽  
Vol 24 (5) ◽  
pp. 617-632 ◽  
Author(s):  
Nahuel Romero ◽  
Catherine I. Dumur ◽  
Hernán Martinez ◽  
Iris A. García ◽  
Pablo Monetta ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hela Cells ◽  
Membrane Trafficking ◽  
Mitogen Activated Protein Kinase ◽  
Thyroid Cell ◽  
Transcriptional Level ◽  
Rab Gtpase ◽  
Mrna Levels ◽  
Consensus Binding Site ◽  
Thyroid Cells

Rab1b belongs to the Rab-GTPase family that regulates membrane trafficking and signal transduction systems able to control diverse cellular activities, including gene expression. Rab1b is essential for endoplasmic reticulum–Golgi transport. Although it is ubiquitously expressed, its mRNA levels vary among different tissues. This work aims to characterize the role of the high Rab1b levels detected in some secretory tissues. We report that, in HeLa cells, an increase in Rab1b levels induces changes in Golgi size and gene expression. Significantly, analyses applied to selected genes, KDELR3, GM130 (involved in membrane transport), and the proto-oncogene JUN, indicate that the Rab1b increase acts as a molecular switch to control the expression of these genes at the transcriptional level, resulting in changes at the protein level. These Rab1b-dependent changes require the activity of p38 mitogen-activated protein kinase and the cAMP-responsive element-binding protein consensus binding site in those target promoter regions. Moreover, our results reveal that, in a secretory thyroid cell line (FRTL5), Rab1b expression increases in response to thyroid-stimulating hormone (TSH). Additionally, changes in Rab1b expression in FRTL5 cells modify the specific TSH response. Our results show, for the first time, that changes in Rab1b levels modulate gene transcription and strongly suggest that a Rab1b increase is required to elicit a secretory response.

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