scholarly journals Rab GTPases: Switching to Human Diseases

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 909 ◽  
Author(s):  
Noemi Antonella Guadagno ◽  
Cinzia Progida
Keyword(s):  
Membrane Trafficking ◽  
Intracellular Transport ◽  
Small Gtpases ◽  
Regulatory Proteins ◽  
Human Diseases ◽  
Rab Proteins ◽  
Rab Gtpases ◽  
Intracellular Membrane ◽  
And Migration ◽  
And Control

Rab proteins compose the largest family of small GTPases and control the different steps of intracellular membrane traffic. More recently, they have been shown to also regulate cell signaling, division, survival, and migration. The regulation of these processes generally occurs through recruitment of effectors and regulatory proteins, which control the association of Rab proteins to membranes and their activation state. Alterations in Rab proteins and their effectors are associated with multiple human diseases, including neurodegeneration, cancer, and infections. This review provides an overview of how the dysregulation of Rab-mediated functions and membrane trafficking contributes to these disorders. Understanding the altered dynamics of Rabs and intracellular transport defects might thus shed new light on potential therapeutic strategies.

Targeting of Rab GTPases to cellular membranes

2005 ◽  
Vol 33 (4) ◽  
pp. 652-656 ◽  
Author(s):  
B.R. Ali ◽  
M.C. Seabra
Keyword(s):  
Membrane Trafficking ◽  
Cellular Localization ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Small Gtpases ◽  
Rab Proteins ◽  
Rab Gtpases ◽  
Cellular Membranes ◽  
Structural Determinants ◽  
Cellular Processes

Rab proteins are members of the superfamily of Ras-like small GTPases and are involved in several cellular processes relating to membrane trafficking and organelle mobility throughout the cell. Like other small GTPases, Rab proteins are initially synthesized as soluble proteins and for membrane attachment they require the addition of lipid moiety(ies) to specific residues of their polypeptide chain. Despite their well-documented roles in regulating cellular trafficking, Rab proteins own trafficking is still poorly understood. We still need to elucidate the molecular mechanisms of their recruitment to cellular membranes and the structural determinants for their specific cellular localization. Recent results indicate that Rab cellular targeting might be Rab-dependent, and this paper briefly reviews our current knowledge of this process.

The Rab family of proteins: 25 years on

2012 ◽  
Vol 40 (6) ◽  
pp. 1337-1347 ◽  
Author(s):  
Eoin E. Kelly ◽  
Conor P. Horgan ◽  
Bruno Goud ◽  
Mary W. McCaffrey
Keyword(s):  
Membrane Trafficking ◽  
Structural Features ◽  
Regulatory Proteins ◽  
Membrane Association ◽  
Rab Gtpase ◽  
Rab Proteins ◽  
Intracellular Membrane ◽  
Vesicle Budding ◽  
Functional Roles

Intracellular membrane trafficking requires the complex interplay of several classes of trafficking proteins. Rab proteins, the largest subfamily of the Ras superfamily of small G-proteins, are central regulators of all aspects of intracellular trafficking processes including vesicle budding and uncoating, motility, tethering and fusion. In the present paper, we discuss the discovery, evolution and characterization of the Rab GTPase family. We examine their basic functional roles, their important structural features and the regulatory proteins which mediate Rab function. We speculate on outstanding issues in the field, such as the mechanisms of Rab membrane association and the co-ordinated interplay between distinct Rab proteins. Finally, we summarize the data implicating Rab proteins in an ever increasing number of diseases.

scholarly journals The Regulation of Rab GTPases by Phosphorylation

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1340
Author(s):  
Lejia Xu ◽  
Yuki Nagai ◽  
Yotaro Kajihara ◽  
Genta Ito ◽  
Taisuke Tomita
Keyword(s):  
Small Gtpases ◽  
Guanine Nucleotide Exchange Factors ◽  
Effector Proteins ◽  
Regulatory Proteins ◽  
Rab Proteins ◽  
Rab Gtpases ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Gtpase Activating Proteins

Rab proteins are small GTPases that act as molecular switches for intracellular vesicle trafficking. Although their function is mainly regulated by regulatory proteins such as GTPase-activating proteins and guanine nucleotide exchange factors, recent studies have shown that some Rab proteins are physiologically phosphorylated in the switch II region by Rab kinases. As the switch II region of Rab proteins undergoes a conformational change depending on the bound nucleotide, it plays an essential role in their function as a ‘switch’. Initially, the phosphorylation of Rab proteins in the switch II region was shown to inhibit the association with regulatory proteins. However, recent studies suggest that it also regulates the binding of Rab proteins to effector proteins, determining which pathways to regulate. These findings suggest that the regulation of the Rab function may be more dynamically regulated by phosphorylation than just through the association with regulatory proteins. In this review, we summarize the recent findings and discuss the physiological and pathological roles of Rab phosphorylation.

scholarly journals Interactions of Lipid Droplets with the Intracellular Transport Machinery

2021 ◽  
Vol 22 (5) ◽  
pp. 2776
Author(s):  
Selma Yilmaz Dejgaard ◽  
John F. Presley
Keyword(s):  
Membrane Trafficking ◽  
Lipid Droplets ◽  
Intracellular Transport ◽  
Neutral Lipids ◽  
Small Gtpases ◽  
Lipid Phase ◽  
Intracellular Organelles ◽  
And Function ◽  
Lipid Phase Separation ◽  
Endocytic Pathways

Historically, studies of intracellular membrane trafficking have focused on the secretory and endocytic pathways and their major organelles. However, these pathways are also directly implicated in the biogenesis and function of other important intracellular organelles, the best studied of which are peroxisomes and lipid droplets. There is a large recent body of work on these organelles, which have resulted in the introduction of new paradigms regarding the roles of membrane trafficking organelles. In this review, we discuss the roles of membrane trafficking in the life cycle of lipid droplets. This includes the complementary roles of lipid phase separation and proteins in the biogenesis of lipid droplets from endoplasmic reticulum (ER) membranes, and the attachment of mature lipid droplets to membranes by lipidic bridges and by more conventional protein tethers. We also discuss the catabolism of neutral lipids, which in part results from the interaction of lipid droplets with cytosolic molecules, but with important roles for both macroautophagy and microautophagy. Finally, we address their eventual demise, which involves interactions with the autophagocytotic machinery. We pay particular attention to the roles of small GTPases, particularly Rab18, in these processes.

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 Spatiotemporal Control of Intracellular Membrane Trafficking by Rho GTPases

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1478 ◽  
Author(s):  
Monilola A. Olayioye ◽  
Bettina Noll ◽  
Angelika Hausser
Keyword(s):  
Membrane Trafficking ◽  
Rho Gtpases ◽  
Rho Gtpase ◽  
Regulatory Proteins ◽  
Biological Processes ◽  
Intracellular Membrane ◽  
Master Regulators ◽  
Cytoskeletal Remodeling ◽  
Wide Range ◽  
Spatiotemporal Control

As membrane-associated master regulators of cytoskeletal remodeling, Rho GTPases coordinate a wide range of biological processes such as cell adhesion, motility, and polarity. In the last years, Rho GTPases have also been recognized to control intracellular membrane sorting and trafficking steps directly; however, how Rho GTPase signaling is regulated at endomembranes is still poorly understood. In this review, we will specifically address the local Rho GTPase pools coordinating intracellular membrane trafficking with a focus on the endo- and exocytic pathways. We will further highlight the spatiotemporal molecular regulation of Rho signaling at endomembrane sites through Rho regulatory proteins, the GEFs and GAPs. Finally, we will discuss the contribution of dysregulated Rho signaling emanating from endomembranes to the development and progression of cancer.

scholarly journals Phosphorylation of Ser111 in Rab8a modulates Rabin8 dependent activation by perturbation of side chain interaction networks

2019 ◽  
Author(s):  
Danial Pourjafar-Dehkordi ◽  
Sophie Vieweg ◽  
Aymelt Itzen ◽  
Martin Zacharias
Keyword(s):  
Intracellular Transport ◽  
Intramolecular Interaction ◽  
Salt Bridge ◽  
Small Gtpases ◽  
Side Chain ◽  
Rab Proteins ◽  
Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Energy Simulations

AbstractGTPases are key-players in cellular signaling processes. Phosphorylation of Rab proteins, which belong to the Ras superfamily of small GTPases regulating intracellular transport, has recently been implicated in the pathogenesis of Parkinson Disease (PD). For Rab8a, it was shown that serine 111 phosphorylation (pS111) is dependent on the protein kinase PINK1, and that mimicking the phosphorylation at S111 by a serine/glutamate substitution (S111E) impaired Rab8a activation by its cognate nucleotide exchange factor (GEF) Rabin8. Here, we performed comparative Molecular Dynamics and free energy simulations on Rab8a and Rab8a:Rabin8 complexes to elucidate the molecular details on how pS111 and S111E may influence the interaction with Rabin8. The simulations indicate that S111E and pS111 establish an intramolecular interaction with arginine 79 (R79). In the complex, this interaction persists, and therefore perturbs a favorable intermolecular salt-bridge contact between R79 in Rab8a and the acidic aspartate 187 (D187) in Rabin8. Binding free analysis reveals that S111E and pS111, as well as the mutation R79A, in Rab8a drastically reduce the binding affinity to Rabin8. Combining the R79A mutation with S111E or pS111, respectively, nearly diminishes Rab8a-Rabin8 binding. In vitro experiments confirm our computational results showing that the nucleotide exchange rates of the respective Rab8a mutants are decreased by >80% in the presence of Rabin8 compared to wild type. In addition to specific insights into how S111 phosphorylation of Rab8a can influence GEF-mediated activation, the simulations demonstrate how side chain modifications in general can allosterically influence the network of surface side chain interactions between binding partners.

scholarly journals Towards a Targeted Therapy:Phosphoproteomics Reveals Signaling Pathways That Are Normalized in AML Cells Following Treatment with Anti-CD44 Antibodies

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1402-1402
Author(s):  
Heba M. Jalal El-Din ◽  
Jasmeen S. Merzaban
Keyword(s):  
Signaling Pathways ◽  
Protein Interactions ◽  
Membrane Trafficking ◽  
Molecular Mechanisms ◽  
Isotope Labeling ◽  
Conflicts Of Interest ◽  
Small Gtpases ◽  
Major Pathway ◽  
Hl60 Cells ◽  
And Control

Abstract Acute myeloid leukemia (AML) is a clonal malignant disease characterized by a blockage in the differentiation of myeloid cells resulting in the accumulation of highly proliferating immature blast cells. With the success of All Trans Retinoic acid (ATRA) in acute promyelocytic leukemia (AML3), differentiation therapy has become a very attractive treatment option. Ligation of CD44 (a cell surface antigen) with anti-CD44 monoclonal antibodies (mAbs) is reported to reverse the blockage of differentiation and suppress the proliferation of blasts derived from most AML subtypes. However, the molecular mechanisms underlying this apparent 'normalization' (reversal) of AML cells induced by CD44 have not been fully elucidated. To expand our understanding of the cellular regulation and circuitry involved, we aimed to apply a quantitative phosphoproteomic approach using Stable Isotope Labeling with Amino acids in Cell culture (SILAC) to monitor dynamic changes of phosphorylation states in HL60 cells following treatment with CD44 mAbs. Phosphoproteomic analysis identified differentially phosphorylated proteins among CD44 mAb treated and control HL60 cells that are involved in a number of major signaling pathways as determined by the Ingenuity Pathway analysis (IPA) platform. Among others, Rho signaling emerged as a major pathway significantly changed by CD44 mAb treatment. Rho GTPases are well-recognized regulators of the actin cytoskeleton but have also been implicated in diverse cellular events such as cell polarity, microtubule dynamics, membrane trafficking, transcriptional regulation, cell growth control and development. An interesting Rho family member, PAK-2 was identified in our search. PAK-2 is a ubiquitously expressed serine/threonine protein kinase, which is a direct target for small GTPases and has been identified as a switch between cell survival and cell death signaling depending on its mode of activation. Western-blot analysis of cell lysates of CD44 mAb treated and control HL60 cells confirmed that the phosphorylation of Pak-2 was altered as early as 5 minutes following treatment. Further validation and characterization of the activation mode, phosphorylation dynamics and protein-protein interactions of PAK-2 are essential in understanding its role in AML. Disclosures No relevant conflicts of interest to declare.

scholarly journals FgRab5 and FgRab7 are essential for endosomes biogenesis and non-redundantly recruit the retromer complex to the endosomes in Fusarium graminearum

2021 ◽  
Vol 1 (1) ◽  
Author(s):  
Yakubu Saddeeq Abubakar ◽  
Han Qiu ◽  
Wenqin Fang ◽  
Huawei Zheng ◽  
Guodong Lu ◽  
...  
Keyword(s):  
Fusarium Graminearum ◽  
Retrograde Transport ◽  
Small Gtpases ◽  
Rab Proteins ◽  
Rab Gtpases ◽  
Wild Type ◽  
Retromer Complex ◽  
Cargo Proteins ◽  
Endosomal Membranes ◽  
In The Wild

AbstractThe retromer complex, composed of the cargo-selective complex (CSC) Vps35-Vps29-Vps26 in complex with the sorting nexin dimer Vps5-Vps17, mediates the sorting and retrograde transport of cargo proteins from the endosomes to the trans-Golgi network in eukaryotic cells. Rab proteins belong to the Ras superfamily of small GTPases and regulate many trafficking events including vesicle formation, budding, transport, tethering, docking and fusion with target membranes. Herein, we investigated the potential functional relationship between the retromer complex and the 11 Rab proteins that exist in Fusarium graminearum using genetic and high-resolution laser confocal microscopic approaches. We found that only FgRab5 (FgRab5A and FgRab5B) and FgRab7 associate with the retromer complex. Both FgVps35-GFP and FgVps17-GFP are mis-localized and appear diffused in the cytoplasm of ΔFgrab5A, ΔFgrab5B and ΔFgrab7 mutants as compared to their punctate localization within the endosomes of the wild-type. FgRab7 and FgRab5B were found to co-localize with the retromer on endosomal membranes. Most strikingly, we found that these three Rab GTPases are indispensable for endosome biogenesis as both early and late endosomes could not be detected in the cells of the mutants after FM4-64 staining of the cells, while they were very clearly seen in the wild-type PH-1. Furthermore, FgRab7 was found to recruit FgVps35 but not FgVps17 to the endosomal membranes, whereas FgRab5B recruits both FgVps35 and FgVps17 to the membranes. Thus, we conclude that the Rab proteins FgRab5A, FgRab5B and FgRab7 play critical roles in the biogenesis of endosomes and in regulating retromer-mediated trafficking in F. graminearum.

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