The Emerging Role of Rab5 in Membrane Receptor Trafficking and Signaling Pathways

Yuan, Wei; Song, Chunli

doi:10.1155/2020/4186308

Cited by 57 publications

(38 citation statements)

References 110 publications

(110 reference statements)

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“…The Ras-related protein Rab5 is a small GTPase that is a major regulator of early steps of endocytosis, and subsequent endosomal membrane trafficking, sorting and endosomal fusion [47][48][49]. Further, through interacting with effector proteins Rab5 has a critical role in regulating the docking and fusion of endosomal membranes, endosomal mobility and intracellular signal transduction [48,50].…”

Section: Overview Of Rab5 Rolesmentioning

confidence: 99%

“…Rab5 effector protein include EEA1 (early endosomal autoantigen 1), APPL (adaptor protein, phosphotyrosine interacting with pleckstrin homology (PH) domain and leucine zipper 1), PI3K (phosphatidylinositol-3-kinase), Rabenosyn-5/hVPS45 (human Sec1p-like vacuolar protein sorting), or Rabaptin-5/Rabex-5, among others. Additionally, a role of Rab5 in regulating the internalization and trafficking of membrane receptors by regulating vesicle fusion and receptor sorting in the early endosomes is emerging [49]. Rab5, which actually comprises three different isoforms, is among the best characterized endosomal markers, in part because of its abundant expression and ubiquitous tissue distribution, including neurons [51,52].…”

Section: Overview Of Rab5 Rolesmentioning

confidence: 99%

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P38α MAPK Signaling—A Robust Therapeutic Target for Rab5-Mediated Neurodegenerative Disease

Germann¹,

Alam²

2020

IJMS

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Multifactorial pathologies, involving one or more aggregated protein(s) and neuroinflammation are common in major neurodegenerative diseases, such as Alzheimer’s disease and dementia with Lewy bodies. This complexity of multiple pathogenic drivers is one potential explanation for the lack of success or, at best, the partial therapeutic effects, respectively, with approaches that have targeted one specific driver, e.g., amyloid-beta, in Alzheimer’s disease. Since the endosome-associated protein Rab5 appears to be a convergence point for many, if not all the most prominent pathogenic drivers, it has emerged as a major therapeutic target for neurodegenerative disease. Further, since the alpha isoform of p38 mitogen-activated protein kinase (p38α) is a major regulator of Rab5 activity and its effectors, a biology that is distinct from the classical nuclear targets of p38 signaling, brain-penetrant selective p38α kinase inhibitors provide the opportunity for significant therapeutic advances in neurogenerative disease through normalizing dysregulated Rab5 activity. In this review, we provide a brief summary of the role of Rab5 in the cell and its association with neurodegenerative disease pathogenesis. We then discuss the connection between Rab5 and p38α and summarize the evidence that through modulating Rab5 activity there are therapeutic opportunities in neurodegenerative diseases for p38α kinase inhibitors.

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Section: Overview Of Rab5 Rolesmentioning

confidence: 99%

Section: Overview Of Rab5 Rolesmentioning

confidence: 99%

P38α MAPK Signaling—A Robust Therapeutic Target for Rab5-Mediated Neurodegenerative Disease

Germann¹,

Alam²

2020

IJMS

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“…Trafficking of RTK-containing vesicles is regulated by the Rab family of monomeric small GTPases, which control vesicle fusion events [ 91 ]. Rab5 regulates fusion events during endocytosis of activated RTKs, important for transportation of the receptor complex from the plasma membrane to early endosomes.…”

Section: Pi3k-independent Roles Of the Class Ia Pi3k Regulatory Subunmentioning

confidence: 99%

“…The GTP-bound Rab proteins localise to early endosomes, binding to the early endosome autoantigen 1 (EEA1) to mediate membrane fusion events. Rab·GDP cannot bind EEA1 making the GTPase activity of Rab4 and 5 the rate-limiting component of early endocytic fusion events [ 91 , 93 ]. The roles of Rab5 and Rab4 in regulating trafficking of internalised RTK complexes via the endocytic pathway, in turn control the subcellular localisation, magnitude and duration of receptor signalling.…”

Section: Pi3k-independent Roles Of the Class Ia Pi3k Regulatory Subunmentioning

confidence: 99%

Class IA PI3K regulatory subunits: p110-independent roles and structures

Fox

Mott

Owen

2020

Biochemical Society Transactions

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The phosphatidylinositol 3-kinase (PI3K) pathway is a critical regulator of many cellular processes including cell survival, growth, proliferation and motility. Not surprisingly therefore, the PI3K pathway is one of the most frequently mutated pathways in human cancers. In addition to their canonical role as part of the PI3K holoenzyme, the class IA PI3K regulatory subunits undertake critical functions independent of PI3K. The PI3K regulatory subunits exist in excess over the p110 catalytic subunits and therefore free in the cell. p110-independent p85 is unstable and exists in a monomer-dimer equilibrium. Two conformations of dimeric p85 have been reported that are mediated by N-terminal and C-terminal protein domain interactions, respectively. The role of p110-independent p85 is under investigation and it has been found to perform critical adaptor functions, sequestering or influencing compartmentalisation of key signalling proteins. Free p85 has roles in glucose homeostasis, cellular stress pathways, receptor trafficking and cell migration. As a regulator of fundamental pathways, the amount of p110-independent p85 in the cell is critical. Factors that influence the monomer-dimer equilibrium of p110-independent p85 offer additional control over this system, disruption to which likely results in disease. Here we review the current knowledge of the structure and functions of p110-independent class IA PI3K regulatory subunits.

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“…Each Rab protein can be recruited to specific membrane subdomains of a defined organelle and is associated to multiple effectors controlling membrane fusion and trafficking. Rab interaction with the membrane fusion complexes and cytoskeleton regulators is therefore crucial for cellular functions, including endocytosis and autophagy ( Chen and Wandinger-Ness, 2001 ; Bruce et al, 2010 ; Geng et al, 2010 ; Thomas and Fromme, 2020 ; Yuan and Song, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

The RUFYs, a Family of Effector Proteins Involved in Intracellular Trafficking and Cytoskeleton Dynamics

Char

Pierre

2020

Front. Cell Dev. Biol.

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Intracellular trafficking is essential for cell structure and function. In order to perform key tasks such as phagocytosis, secretion or migration, cells must coordinate their intracellular trafficking, and cytoskeleton dynamics. This relies on certain classes of proteins endowed with specialized and conserved domains that bridge membranes with effector proteins. Of particular interest are proteins capable of interacting with membrane subdomains enriched in specific phosphatidylinositol lipids, tightly regulated by various kinases and phosphatases. Here, we focus on the poorly studied RUFY family of adaptor proteins, characterized by a RUN domain, which interacts with small GTP-binding proteins, and a FYVE domain, involved in the recognition of phosphatidylinositol 3-phosphate. We report recent findings on this protein family that regulates endosomal trafficking, cell migration and upon dysfunction, can lead to severe pathology at the organismal level.

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The Emerging Role of Rab5 in Membrane Receptor Trafficking and Signaling Pathways

Cited by 57 publications

References 110 publications

P38α MAPK Signaling—A Robust Therapeutic Target for Rab5-Mediated Neurodegenerative Disease

P38α MAPK Signaling—A Robust Therapeutic Target for Rab5-Mediated Neurodegenerative Disease

Class IA PI3K regulatory subunits: p110-independent roles and structures

The RUFYs, a Family of Effector Proteins Involved in Intracellular Trafficking and Cytoskeleton Dynamics

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