scholarly journals Involvement of Rac/Cdc42/PAK pathway in cytoskeletal rearrangements.

2009 ◽  
Vol 56 (2) ◽  
Author(s):  
Joanna Szczepanowska
Keyword(s):  
Neurodegenerative Diseases ◽  
Protein Kinases ◽  
Small Gtpases ◽  
Cytoskeletal Reorganization ◽  
Cellular Processes ◽  
Cytoskeletal Structure ◽  
Binding Partners ◽  
Evolutionarily Conserved ◽  
Cytoskeletal Rearrangements

The p21-activated kinases (PAKs) are serine/threonine protein kinases interacting with small GTPases - Rac and Cdc42. PAKs are found in most eukaryotes and play an evolutionarily conserved role in many cellular processes. Six human PAKs have been identified, and based on homology, they can be classified into two groups. This review focuses specifically on the role of Rac/Cdc42 regulated PAKs in maintaining and remodeling cytoskeletal structure in various organisms. A list of PAKs substrates and binding partners implicated directly and indirectly in cytoskeletal reorganization is presented. Also perturbations of the Rac/Cdc42/PAK pathway leading to tumorigenesis and neurodegenerative diseases are reviewed.

Differential targeting of cPKC and nPKC decodes and regulates Ca2+ and lipid signalling

2014 ◽  
Vol 42 (6) ◽  
pp. 1538-1542 ◽  
Author(s):  
Xin Hui ◽  
Lars Kaestner ◽  
Peter Lipp
Keyword(s):  
Protein Kinases ◽  
Consensus Sequence ◽  
Membrane Targeting ◽  
Cellular Processes ◽  
Lipid Signalling ◽  
Pkc Isoforms

Protein kinases C (PKCs) are ubiquitously expressed and play critical roles in a plethora of physiological and pathophysiological processes. Owing to PKCs’ highly conserved phosphorylation consensus sequence, it has been difficult to distinguish the role of individual PKC isoforms. Recently, the identification of novel membrane targeting via subcellularly targeted diacylglycerol production found for novel PKCs (nPKCs), together with a characterization of their putative functions, has shed new light on the specific roles of individual PKCs in cellular processes.

scholarly journals The Golgi apparatus in neurorestoration

2019 ◽  
Vol 7 (3) ◽  
pp. 116-128
Author(s):  
Jianyang Liu ◽  
Jialin He ◽  
Yan Huang ◽  
Han Xiao ◽  
Zheng Jiang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Golgi Apparatus ◽  
Neurodegenerative Diseases ◽  
Disease Progression ◽  
Neurological Recovery ◽  
Cellular Processes ◽  
Wide Range ◽  
And Oxidative Stress

The central role of the Golgi apparatus in critical cellular processes such as the transport, processing, and sorting of proteins and lipids has placed it at the forefront of cell science. Golgi apparatus dysfunction caused by primary defects within the Golgi or pharmacological and oxidative stress has been implicated in a wide range of neurodegenerative diseases. In addition to participating in disease progression, the Golgi apparatus plays pivotal roles in angiogenesis, neurogenesis, and synaptogenesis, thereby promoting neurological recovery. In this review, we focus on the functions of the Golgi apparatus and its mediated events during neurorestoration.

scholarly journals Structural Insights into the Evolutionarily Conserved BAF Chromatin Remodeling Complex

Biology ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 146
Author(s):  
Ryan D. Marcum ◽  
Alexis A. Reyes ◽  
Yuan He
Keyword(s):  
High Frequency ◽  
Human Cancer ◽  
Chromatin Accessibility ◽  
Baf Complex ◽  
Cellular Processes ◽  
Chromatin Remodeling Complex ◽  
Evolutionarily Conserved ◽  
Potential Impact ◽  
Structural Insights

The switch/sucrose nonfermentable (SWI/SNF) family of proteins acts to regulate chromatin accessibility and plays an essential role in multiple cellular processes. A high frequency of mutations has been found in SWI/SNF family subunits by exome sequencing in human cancer, and multiple studies support its role in tumor suppression. Recent structural studies of yeast SWI/SNF and its human homolog, BAF (BRG1/BRM associated factor), have provided a model for their complex assembly and their interaction with nucleosomal substrates, revealing the molecular function of individual subunits as well as the potential impact of cancer-associated mutations on the remodeling function. Here we review the structural conservation between yeast SWI/SNF and BAF and examine the role of highly mutated subunits within the BAF complex.

scholarly journals Dynamin and endocytosis are required for the fusion of osteoclasts and myoblasts

2014 ◽  
Vol 207 (1) ◽  
pp. 73-89 ◽  
Author(s):  
Nah-Young Shin ◽  
Hyewon Choi ◽  
Lynn Neff ◽  
Yumei Wu ◽  
Hiroaki Saito ◽  
...  
Keyword(s):  
Cell Fusion ◽  
Knockout Mouse ◽  
Cell Types ◽  
Cytoskeletal Reorganization ◽  
Knockout Mouse Model ◽  
Osteoclast Precursors ◽  
Evolutionarily Conserved ◽  
Myoblast Cell ◽  
Cell Cell

Cell–cell fusion is an evolutionarily conserved process that leads to the formation of multinucleated myofibers, syncytiotrophoblasts and osteoclasts, allowing their respective functions. Although cell–cell fusion requires the presence of fusogenic membrane proteins and actin-dependent cytoskeletal reorganization, the precise machinery allowing cells to fuse is still poorly understood. Using an inducible knockout mouse model to generate dynamin 1– and 2–deficient primary osteoclast precursors and myoblasts, we found that fusion of both cell types requires dynamin. Osteoclast and myoblast cell–cell fusion involves the formation of actin-rich protrusions closely associated with clathrin-mediated endocytosis in the apposed cell. Furthermore, impairing endocytosis independently of dynamin also prevented cell–cell fusion. Since dynamin is involved in both the formation of actin-rich structures and in endocytosis, our results indicate that dynamin function is central to the osteoclast precursors and myoblasts fusion process, and point to an important role of endocytosis in cell–cell fusion.

scholarly journals DYRK1A Autophosphorylation on Serine Residue 520 Modulates Its Kinase Activity via 14-3-3 Binding

2007 ◽  
Vol 18 (4) ◽  
pp. 1167-1178 ◽  
Author(s):  
Mónica Alvarez ◽  
Xavier Altafaj ◽  
Sergi Aranda ◽  
Susana de la Luna
Keyword(s):  
Protein Kinases ◽  
Kinase Activity ◽  
Dynamic Changes ◽  
Activated T Cells ◽  
Cellular Processes ◽  
Dual Specificity ◽  
Evolutionarily Conserved ◽  
The Family ◽  
Intramolecular Mechanism

Dual-specificity tyrosine-phosphorylated and regulated kinase (DYRK) proteins are an evolutionarily conserved family of protein kinases, with members identified from yeast to humans, that participate in a variety of cellular processes. DYRKs are serine/threonine protein kinases that are activated by autophosphorylation on a tyrosine residue in the activation loop. The family member DYRK1A has been shown to phosphorylate several cytosolic proteins and a number of splicing and transcription factors, including members of the nuclear factor of activated T cells family. In the present study, we show that DYRK1A autophosphorylates, via an intramolecular mechanism, on Ser-520, in the PEST domain of the protein. We also show that phosphorylation of this residue, which we show is subjected to dynamic changes in vivo, mediates the interaction of DYRK1A with 14-3-3β. A second 14-3-3 binding site is present within the N-terminal of the protein. In the context of the DYRK1A molecule, neither site can act independently of the other. Bacterially produced DYRK1A and the mutant DYRK1A/S520A have similar kinase activities, suggesting that Ser-520 phosphorylation does not affect the intrinsic kinase activity on its own. Instead, we demonstrate that this phosphorylation allows the binding of 14-3-3β, which in turn stimulates the catalytic activity of DYRK1A. These findings provide evidence for a novel mechanism for the regulation of DYRK1A kinase activity.

scholarly journals BAG3 regulation of Rab35 mediates the ESCRT/endolysosome pathway and tau clearance

2021 ◽  
Author(s):  
Heng Lin ◽  
Maoping Tang ◽  
Changyi Ji ◽  
Peter Girardi ◽  
Gregor Cvetojevic ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Small Gtpases ◽  
Endocytic Pathway ◽  
Gtpase Activating Protein ◽  
Dependent Protein ◽  
Autophagy Pathway ◽  
Increased Susceptibility

AbstractThe decline in proteostasis during aging is a major contributing factor to increased susceptibility to neurodegenerative diseases such as Alzheimer’s disease. Although dysfunction of the autophagy pathway is likely one of the contributors, emerging studies implicate that impairment of the endosome-lysosome pathway is also a significant factor in the pathogenesis of these diseases. Our lab was the first to demonstrate that BAG3 facilitates phosphorylated tau clearance through autophagy. However, we did not fully define the mechanisms by which BAG3 regulates endogenous tau proteostasis. Here, we applied mass spectrometric analyses and found a major group of neuronal BAG3 interactors are in the endocytic pathway. Among them were key regulators of small GTPases. Excitingly one of these was the Rab35 GTPase activating protein, TBC1D10B. Our data demonstrate that a BAG3-HSP70-TBC1D10B complex attenuates the ability of TBC1D10B to inactivate Rab35. Thus BAG3, through its interaction with TBC1D10B supports the activation of Rab35 and recruitment of Hrs, which initiates ESCRT-mediated endosomal tau clearance. Further, intrahippocampal expression of BAG3 in P301S mice increased the co-localization of phospho-tau with the ESCRT III protein CHMP2B and reduced the levels of the mutant human tau. Overall, our data provide evidence of a novel BAG3-TBC1D10B-Rab35 regulatory axis in modulating vacuolar dependent protein degradation machinery through ESCRT. These findings expand our understanding of the role of BAG3 in neuronal proteostasis, and how dysregulation could contribute to the pathogenesis of Alzheimer’s disease, as well as other neurodegenerative diseases.

scholarly journals mTOR and Aging: An Old Fashioned Dress

2019 ◽  
Vol 20 (11) ◽  
pp. 2774 ◽  
Author(s):  
Giovanni Stallone ◽  
Barbara Infante ◽  
Concetta Prisciandaro ◽  
Giuseppe Grandaliano
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Nutrient Sensing ◽  
Protective Effects ◽  
Cellular Functions ◽  
Cellular Processes ◽  
Age Related ◽  
Signalling Network ◽  
Evolutionarily Conserved ◽  
Mtor Signalling

Aging is a physiologic/pathologic process characterized by a progressive impairment of cellular functions, supported by the alterations of several molecular pathways, leading to an increased cell susceptibility to injury. This deterioration is the primary risk factor for several major human pathologies. Numerous cellular processes, including genomic instability, telomere erosion, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, stem cell exhaustion, and altered intercellular signal transduction represent common denominators of aging in different organisms. Mammalian target of rapamycin (mTOR) is an evolutionarily conserved nutrient sensing protein kinase that regulates growth and metabolism in all eukaryotic cells. Studies in flies, worms, yeast, and mice support the hypothesis that the mTOR signalling network plays a pivotal role in modulating aging. mTOR is emerging as the most robust mediator of the protective effects of various forms of dietary restriction, which has been shown to extend lifespan and slow the onset of age-related diseases across species. Herein we discuss the role of mTor signalling network in the development of classic age-related diseases, focused on cardiovascular system, immune response, and cancer.

scholarly journals Oxidative Stress in Neurodegenerative Diseases: From a Mitochondrial Point of View

2019 ◽  
Vol 2019 ◽  
pp. 1-18 ◽  
Author(s):  
Giovanna Cenini ◽  
Ana Lloret ◽  
Roberta Cascella
Keyword(s):  
Oxidative Stress ◽  
Neurodegenerative Diseases ◽  
Aging Process ◽  
Molecular Mechanisms ◽  
High Energy ◽  
Point Of View ◽  
Antioxidant Defenses ◽  
Mitochondrial Oxidative Stress ◽  
Cellular Processes

Age is the main risk factor for a number of human diseases, including neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, which increasing numbers of elderly individuals suffer. These pathological conditions are characterized by progressive loss of neuron cells, compromised motor or cognitive functions, and accumulation of abnormally aggregated proteins. Mitochondrial dysfunction is one of the main features of the aging process, particularly in organs requiring a high-energy source such as the heart, muscles, brain, or liver. Neurons rely almost exclusively on the mitochondria, which produce the energy required for most of the cellular processes, including synaptic plasticity and neurotransmitter synthesis. The brain is particularly vulnerable to oxidative stress and damage, because of its high oxygen consumption, low antioxidant defenses, and high content of polyunsaturated fats very prone to be oxidized. Thus, it is not surprising the importance of protecting systems, including antioxidant defenses, to maintain neuronal integrity and survival. Here, we review the role of mitochondrial oxidative stress in the aging process, with a specific focus on neurodegenerative diseases. Understanding the molecular mechanisms involving mitochondria and oxidative stress in the aging and neurodegeneration may help to identify new strategies for improving the health and extending lifespan.

In vivo functions of small GTPases in neocortical development

2014 ◽  
Vol 395 (5) ◽  
pp. 465-476 ◽  
Author(s):  
Bhavin Shah ◽  
Andreas W. Püschel
Keyword(s):  
Neuronal Development ◽  
Small Gtpases ◽  
Neuronal Cultures ◽  
Primary Neuronal Cultures ◽  
Cellular Processes ◽  
Neuronal Progenitors ◽  
Embryonic Nervous System ◽  
And Migration ◽  
Cytoskeletal Rearrangements

Abstract The complex mammalian cortex develops from a simple neuroepithelium through the proliferation of neuronal progenitors, their asymmetric division and cell migration. Newly generated neurons transiently assume a multipolar morphology before they polarize to form a trailing axon and a leading process that is required for their radial migration. The polarization and migration events during cortical development are under the control of multiple signaling cascades that coordinate the different cellular processes involved in neuronal differentiation. GTPases perform essential functions at different stages of neuronal development as central components of these pathways. They have been widely studied using cell lines and primary neuronal cultures but their physiological function in vivo still remains to be explored in many cases. Here we review the function of GTPases that have been studied genetically by the analysis of the embryonic nervous system in knockout mice. The phenotype of these mutants has highlighted the importance of GTPases for different steps of development by orchestrating cytoskeletal rearrangements and neuronal polarization.

scholarly journals The Emerging Role of Proteolysis in Mitochondrial Quality Control and the Etiology of Parkinson’s Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-16 ◽  
Author(s):  
Riya Shanbhag ◽  
Guang Shi ◽  
Jarungjit Rujiviphat ◽  
G. Angus McQuibban
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Quality Control ◽  
Neurodegenerative Diseases ◽  
Mitochondrial Quality Control ◽  
Future Studies ◽  
Cellular Processes ◽  
Different Types ◽  
Calcium Buffering

Mitochondria are highly dynamic organelles that are important for many diverse cellular processes, such as energy metabolism, calcium buffering, and apoptosis. Mitochondrial biology and dysfunction have recently been linked to different types of cancers and neurodegenerative diseases, most notably Parkinson’s disease. Thus, a better understanding of the quality control systems that maintain a healthy mitochondrial network can facilitate the development of effective treatments for these diseases. In this perspective, we will discuss recent advances on two mitochondrial quality control pathways: the UPS and mitophagy, highlight how new players may be contributing to regulate these pathways. We believe the proteases involved will be key and novel regulators of mitochondrial quality control, and this knowledge will provide insights into future studies aimed to combat neurodegenerative diseases.

Sign in / Sign up

Export Citation Format

Share Document