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.

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 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.

scholarly journals Rabs in Signaling and Embryonic Development

2020 ◽  
Vol 21 (3) ◽  
pp. 1064 ◽  
Author(s):  
Sonya Nassari ◽  
Tomas Del Olmo ◽  
Steve Jean
Keyword(s):  
Embryonic Development ◽  
Membrane Trafficking ◽  
Intracellular Signaling ◽  
Rab Proteins ◽  
Rab Gtpases ◽  
Cellular Processes ◽  
Complex Process ◽  
Signaling Events ◽  
And Function

Rab GTPases play key roles in various cellular processes. They are essential, among other roles, to membrane trafficking and intracellular signaling events. Both trafficking and signaling events are crucial for proper embryonic development. Indeed, embryogenesis is a complex process in which cells respond to various signals and undergo dramatic changes in their shape, position, and function. Over the last few decades, cellular studies have highlighted the novel signaling roles played by Rab GTPases, while numerous studies have shed light on the important requirements of Rab proteins at various steps of embryonic development. In this review, we aimed to generate an overview of Rab contributions during animal embryogenesis. We first briefly summarize the involvement of Rabs in signaling events. We then extensively highlight the contribution of Rabs in shaping metazoan development and conclude with new approaches that will allow investigation of Rab functions in vivo.

scholarly journals A Concerted Action of UBA5 C-Terminal Unstructured Regions Is Important for Transfer of Activated UFM1 to UFC1

2021 ◽  
Vol 22 (14) ◽  
pp. 7390
Author(s):  
Nicole Wesch ◽  
Frank Löhr ◽  
Natalia Rogova ◽  
Volker Dötsch ◽  
Vladimir V. Rogov
Keyword(s):  
Cellular Localization ◽  
Molecular Mechanisms ◽  
Biochemical Characterization ◽  
Effective Interaction ◽  
Regulatory Region ◽  
Titration Calorimetry ◽  
Enzymatic Reactions ◽  
Cellular Processes ◽  
Mechanism Of Interaction

Ubiquitin fold modifier 1 (UFM1) is a member of the ubiquitin-like protein family. UFM1 undergoes a cascade of enzymatic reactions including activation by UBA5 (E1), transfer to UFC1 (E2) and selective conjugation to a number of target proteins via UFL1 (E3) enzymes. Despite the importance of ufmylation in a variety of cellular processes and its role in the pathogenicity of many human diseases, the molecular mechanisms of the ufmylation cascade remains unclear. In this study we focused on the biophysical and biochemical characterization of the interaction between UBA5 and UFC1. We explored the hypothesis that the unstructured C-terminal region of UBA5 serves as a regulatory region, controlling cellular localization of the elements of the ufmylation cascade and effective interaction between them. We found that the last 20 residues in UBA5 are pivotal for binding to UFC1 and can accelerate the transfer of UFM1 to UFC1. We solved the structure of a complex of UFC1 and a peptide spanning the last 20 residues of UBA5 by NMR spectroscopy. This structure in combination with additional NMR titration and isothermal titration calorimetry experiments revealed the mechanism of interaction and confirmed the importance of the C-terminal unstructured region in UBA5 for the ufmylation cascade.

scholarly journals The Chinese Medicinal Formulation Guzhi Zengsheng Zhitongwan Modulates Chondrocyte Structure, Dynamics, and Metabolism by Controlling Multiple Functional Proteins

2018 ◽  
Vol 2018 ◽  
pp. 1-12
Author(s):  
Baojin Yao ◽  
Bocheng Lu ◽  
Mei Zhang ◽  
Hongwei Gao ◽  
Xiangyang Leng ◽  
...  
Keyword(s):  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Research Field ◽  
Medical Systems ◽  
Cellular Processes ◽  
Structure Dynamics ◽  
National Medical ◽  
Medicinal Formulation

Traditional Chinese medicine is one of the oldest medical systems in the world and has its unique principles and theories in the prevention and treatment of human diseases, which are achieved through the interactions of different types of materia medica in the form of Chinese medicinal formulations. GZZSZTW, a classical and effective Chinese medicinal formulation, was designed and created by professor Bailing Liu who is the only national medical master professor in the clinical research field of traditional Chinese medicine and skeletal diseases. GZZSZTW has been widely used in clinical settings for several decades for the treatment of joint diseases. However, the underlying molecular mechanisms are still largely unknown. In the present study, we performed quantitative proteomic analysis to investigate the effects of GZZSZTW on mouse primary chondrocytes using state-of-the-art iTRAQ technology. We demonstrated that the Chinese medicinal formulation GZZSZTW modulates chondrocyte structure, dynamics, and metabolism by controlling multiple functional proteins that are involved in the cellular processes of DNA replication and transcription, protein synthesis and degradation, cytoskeleton dynamics, and signal transduction. Thus, this study has expanded the current knowledge of the molecular mechanism of GZZSZTW treatment on chondrocytes. It has also shed new light on possible strategies to further prevent and treat cartilage-related diseases using traditional Chinese medicinal formulations.

scholarly journals Regulation of Rho GTPases in the Vasculature by Cullin3-Based E3 Ligase Complexes

2021 ◽  
Vol 9 ◽  
Author(s):  
Fabienne Podieh ◽  
Peter L. Hordijk
Keyword(s):  
Rho Gtpases ◽  
Vascular Function ◽  
Rho Gtpase ◽  
Current Knowledge ◽  
E3 Ligase ◽  
Small Gtpases ◽  
E3 Ligases ◽  
Cellular Processes ◽  
Ubiquitin E3 Ligase ◽  
Cytoskeletal Dynamics

Cullin3-based ubiquitin E3 ligases induce ubiquitination of substrates leading to their proteasomal or lysosomal degradation. BTB proteins serve as adaptors by binding to Cullin3 and recruiting substrate proteins, which enables specific recognition of a broad spectrum of targets. Hence, Cullin3 and its adaptors are involved in myriad cellular processes and organ functions. Cullin3-based ubiquitin E3 ligase complexes target small GTPases of the Rho subfamily, which are key regulators of cytoskeletal dynamics and cell adhesion. In this mini review, we discuss recent insights in Cullin3-mediated regulation of Rho GTPases and their impact on cellular function and disease. Intriguingly, upstream regulators of Rho GTPases are targeted by Cullin3 complexes as well. Thus, Rho GTPase signaling is regulated by Cullin3 on multiple levels. In addition, we address current knowledge of Cullin3 in regulating vascular function, focusing on its prominent role in endothelial barrier function, angiogenesis and the regulation of blood pressure.

scholarly journals Lysosomal Exocytosis, Exosome Release and Secretory Autophagy: The Autophagic- and Endo-Lysosomal Systems Go Extracellular

2020 ◽  
Vol 21 (7) ◽  
pp. 2576 ◽  
Author(s):  
Sandra Buratta ◽  
Brunella Tancini ◽  
Krizia Sagini ◽  
Federica Delo ◽  
Elisabetta Chiaradia ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Cell Communication ◽  
Lysosomal Storage ◽  
Cellular Processes ◽  
Age Related ◽  
Extracellular Release ◽  
A Cell ◽  
Endosomal System

Beyond the consolidated role in degrading and recycling cellular waste, the autophagic- and endo-lysosomal systems play a crucial role in extracellular release pathways. Lysosomal exocytosis is a process leading to the secretion of lysosomal content upon lysosome fusion with plasma membrane and is an important mechanism of cellular clearance, necessary to maintain cell fitness. Exosomes are a class of extracellular vesicles originating from the inward budding of the membrane of late endosomes, which may not fuse with lysosomes but be released extracellularly upon exocytosis. In addition to garbage disposal tools, they are now considered a cell-to-cell communication mechanism. Autophagy is a cellular process leading to sequestration of cytosolic cargoes for their degradation within lysosomes. However, the autophagic machinery is also involved in unconventional protein secretion and autophagy-dependent secretion, which are fundamental mechanisms for toxic protein disposal, immune signalling and pathogen surveillance. These cellular processes underline the crosstalk between the autophagic and the endosomal system and indicate an intersection between degradative and secretory functions. Further, they suggest that the molecular mechanisms underlying fusion, either with lysosomes or plasma membrane, are key determinants to maintain cell homeostasis upon stressing stimuli. When they fail, the accumulation of undigested substrates leads to pathological consequences, as indicated by the involvement of autophagic and lysosomal alteration in human diseases, namely lysosomal storage disorders, age-related neurodegenerative diseases and cancer. In this paper, we reviewed the current knowledge on the functional role of extracellular release pathways involving lysosomes and the autophagic- and endo-lysosomal systems, evaluating their implication in health and disease.

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 Chromatin dynamics during interphase and cell division: similarities and differences between model and crop plants

2019 ◽  
Vol 71 (17) ◽  
pp. 5205-5222 ◽  
Author(s):  
Ales Pecinka ◽  
Christian Chevalier ◽  
Isabelle Colas ◽  
Kriton Kalantidis ◽  
Serena Varotto ◽  
...  
Keyword(s):  
Genetic Information ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Crop Plants ◽  
Regulatory Proteins ◽  
Abiotic And Biotic Stresses ◽  
Chromatin Dynamics ◽  
Biotic Stresses ◽  
Cellular Processes ◽  
Organismal Development

Abstract Genetic information in the cell nucleus controls organismal development and responses to the environment, and finally ensures its own transmission to the next generations. To achieve so many different tasks, the genetic information is associated with structural and regulatory proteins, which orchestrate nuclear functions in time and space. Furthermore, plant life strategies require chromatin plasticity to allow a rapid adaptation to abiotic and biotic stresses. Here, we summarize current knowledge on the organization of plant chromatin and dynamics of chromosomes during interphase and mitotic and meiotic cell divisions for model and crop plants differing as to genome size, ploidy, and amount of genomic resources available. The existing data indicate that chromatin changes accompany most (if not all) cellular processes and that there are both shared and unique themes in the chromatin structure and global chromosome dynamics among species. Ongoing efforts to understand the molecular mechanisms involved in chromatin organization and remodeling have, together with the latest genome editing tools, potential to unlock crop genomes for innovative breeding strategies and improvements of various traits.

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.

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