scholarly journals Mask, the Drosophila Ankyrin Repeat and KH domain-containing protein, affects microtubule stability

2021 ◽  
Author(s):  
Daniel Martinez ◽  
Mingwei Zhu ◽  
Jessie J. Guidry ◽  
Niles Majeste ◽  
Hui Mao ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Neuromuscular Junctions ◽  
Function Analysis ◽  
Normal Function ◽  
Loss Of Function ◽  
Synaptic Growth ◽  
Cellular Processes ◽  
Microtubule Stability ◽  
Kh Domain ◽  
Mask Function

Proper regulation of microtubule (MT) stability and dynamics is vital for essential cellular processes, including axonal transportation and synaptic growth and remodeling in neurons. Here, we demonstrate that Mask negatively affects MT stability in both fly larval muscles and motor neurons. In larval muscles, loss-of-function of mask increases MT polymer length, and in motor neurons, loss of mask function results in overexpansion of the presynaptic terminal at the larval neuromuscular junctions (NMJs). mask genetically interacts with stathmin (stai), a neuronal modulator of MT stability, in the regulation of axon transportation and synaptic terminal stability. Our structure/function analysis on Mask revealed that its Ankyrin Repeats domain-containing N-terminal portion is sufficient to mediate Mask's impact to MT stability. Furthermore, we discovered that Mask negatively regulates the abundance of the microtubule-associated protein Jupiter in motor neuron axons, and that neuronal knocking down of Jupiter partially suppresses mask loss-of-function phenotypes at the larval NMJs. Together, our studies demonstrated that Mask is a novel regulator for microtubule stability, and such a role of Mask requires normal function of Jupiter.

scholarly journals Mask, the Drosophila Ankyrin Repeat and KH domain-containing protein, regulates microtubule dynamics

2020 ◽  
Author(s):  
Mingwei Zhu ◽  
Daniel Martinez ◽  
Jessie J. Guidry ◽  
Niles Majeste ◽  
Hui Mao ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Neuromuscular Junctions ◽  
Genetic Interaction ◽  
Function Analysis ◽  
Underlying Mechanism ◽  
Structural Basis ◽  
Synaptic Growth ◽  
Binding Function ◽  
Proteomic Approach ◽  
Kh Domain

AbstractProper regulation of microtubule (MT) dynamics is vital for essential cellular processes and many neuronal activities, including axonal transport and synaptic growth and remodeling. Here we demonstrate that Mask negatively regulates MT stability and maintains a balanced MT length and architecture in both fly larval muscles and motor neurons. In larval muscles, loss of mask increases MT length, and altering mask genetically modifies the Tau-induced MT fragmentation. In motor neurons, loss of mask function reduces the number of End-Binding Protein 1 (EB1)-positive MT plus-ends in the axons and results in overexpansion of the presynaptic terminal at larval neuromuscular junctions (NMJ). mask shows strong genetic interaction with stathmin (stai), a neuronal modulator of MT dynamics, in regulation of axon transportation and synaptic terminal stability. The structure/function analysis on Mask suggests that Mask’s action in regulating MT stability does not depend on the nucleotide-binding function of its KH domain. Furthermore, through a proteomic approach, we found that Mask physically interacts with Jupiter, an MT stabilizing factor. The MT localization of Jupiter in the axons inversely correlates with Mask levels, suggesting that Mask may modulate MT stability by inhibiting the association of Jupiter to MTs.Author SummaryMicrotubules (MT) are part of the cytoskeleton of the cells that provides essential structural basis for critical processes and functions of the cells. A complex factors are required to orchestrate the assembly and disassembly of MT. Here we identified Mask as a novel regulator for MT dynamics in fruit flies. Mask negatively regulates MT stability. It shows prominent interplay with two important modulators of MT, Tau and Stathmin (Stai), both genes are linked to human neurodegenerative disorders. These findings not only support the role of Mask as a novel microtubule regulator, but also provide foundation to explore future therapeutic strategies in mitigating deficit related to dysfunction of Tau and Stathmin. Our further analysis on Mask protein demonstrate that Mask can physically interacts with another MT stabilizing factor named Jupiter. Jupiter can bind to MT, but its localization to the MTs in the axons is negatively affected by Mask, implying a possible underlying mechanism that Mask may modulate MT stability by inhibiting the association of Jupiter to MTs.

scholarly journals Microtubule stability, Golgi organization, and transport flux require dystonin-a2–MAP1B interaction

2012 ◽  
Vol 196 (6) ◽  
pp. 727-742 ◽  
Author(s):  
Scott D. Ryan ◽  
Kunal Bhanot ◽  
Andrew Ferrier ◽  
Yves De Repentigny ◽  
Alphonse Chu ◽  
...  
Keyword(s):  
Secretory Pathway ◽  
Function Analysis ◽  
Trichostatin A ◽  
Mutant Mice ◽  
Loss Of Function ◽  
Cellular Functions ◽  
Microtubule Stability ◽  
Golgi Fragmentation ◽  
Golgi Organization ◽  
Transport Flux

Loss of function of dystonin cytoskeletal linker proteins causes neurodegeneration in dystonia musculorum (dt) mutant mice. Although much investigation has focused on understanding dt pathology, the diverse cellular functions of dystonin isoforms remain poorly characterized. In this paper, we highlight novel functions of the dystonin-a2 isoform in mediating microtubule (MT) stability, Golgi organization, and flux through the secretory pathway. Using dystonin mutant mice combined with isoform-specific loss-of-function analysis, we found dystonin-a2 bound to MT-associated protein 1B (MAP1B) in the centrosomal region, where it maintained MT acetylation. In dt neurons, absence of the MAP1B–dystonin-a2 interaction resulted in altered MAP1B perikaryal localization, leading to MT deacetylation and instability. Deacetylated MT accumulation resulted in Golgi fragmentation and prevented anterograde trafficking via motor proteins. Maintenance of MT acetylation through trichostatin A administration or MAP1B overexpression mitigated the observed defect. These cellular aberrations are apparent in prephenotype dorsal root ganglia and primary sensory neurons from dt mice, suggesting they are causal in the disorder.

scholarly journals Glia-neuron signaling mediated by two different BMP ligands impacts synaptic growth

2021 ◽  
Author(s):  
Mathieu Bartoletti ◽  
Tracy Knight ◽  
Aaron Held ◽  
Laura M. Rand ◽  
Kristi A. Wharton
Keyword(s):  
Nervous System ◽  
Neuromuscular Junction ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Neural Development ◽  
Growth Function ◽  
Bmp Signaling ◽  
Autocrine Signaling ◽  
Loss Of Function ◽  
Synaptic Growth

ABSTRACTThe nervous system is a complex network of cells whose interactions provide circuitry necessary for an organism to perceive and move through its environment. Revealing the molecular basis of how neurons and non-neuronal glia communicate is essential for understanding neural development, behavior, and abnormalities of the nervous system. BMP signaling in motor neurons, activated in part by retrograde signals from muscle expressed Gbb (BMP5/6/7) has been implicated in synaptic growth, function and plasticity inDrosophila melanogaster. Through loss-of-function studies, we establish Gbb as a critical mediator of glia to neuron signaling important for proper synaptic growth. Furthermore, the BMP2/4 ortholog, Dpp, expressed in a subset of motor neurons, acts by autocrine signaling to also facilitate neuromuscular junction (NMJ) growth at specific muscle innervation sites. In addition to signaling from glia to motor neurons, autocrine Gbb induces signaling in larval VNC glia which strongly express the BMP type II receptor, Wit. In addition to Dpp’s autocrine motor neuron signaling, Dpp also engages in paracrine signaling to adjacent glia but not to neighboring motor neurons. In one type of dorsal midline motor neuron, RP2,dpptranscription is under tight regulation, as its expression is under autoregulatory control in RP2 but not aCC neurons. Taken together our findings indicate that bi-directional BMP signaling, mediated by two different ligands, facilitates communication between glia and neurons. Gbb, prominently expressed in glia, and Dpp acting from a discrete set of neurons induce active Smad-dependent BMP signaling to influence bouton number during neuromuscular junction growth.

scholarly journals Nemo kinase interacts with Mad to coordinate synaptic growth at the Drosophila neuromuscular junction

2009 ◽  
Vol 185 (4) ◽  
pp. 713-725 ◽  
Author(s):  
Carlos Merino ◽  
Jay Penney ◽  
Miranda González ◽  
Kazuya Tsurudome ◽  
Myriam Moujahidine ◽  
...  
Keyword(s):  
Neuromuscular Junction ◽  
Motor Neurons ◽  
Genetic Interaction ◽  
Phosphorylation Site ◽  
Normal Function ◽  
Bmp Signaling ◽  
Structural Defects ◽  
Synaptic Growth ◽  
N Terminus ◽  
Larval Neuromuscular Junction

Bone morphogenic protein (BMP) signaling is essential for the coordinated assembly of the synapse, but we know little about how BMP signaling is modulated in neurons. Our findings indicate that the Nemo (Nmo) kinase modulates BMP signaling in motor neurons. nmo mutants show synaptic structural defects at the Drosophila melanogaster larval neuromuscular junction, and providing Nmo in motor neurons rescues these defects. We show that Nmo and the BMP transcription factor Mad can be coimmunoprecipitated and find a genetic interaction between nmo and Mad mutants. Moreover, we demonstrate that Nmo is required for normal distribution and accumulation of phosphorylated Mad in motor neurons. Finally, our results indicate that Nmo phosphorylation of Mad at its N terminus, distinct from the BMP phosphorylation site, is required for normal function of Mad. Based on our findings, we propose a model in which phosphorylation of Mad by Nmo ensures normal accumulation and distribution of Mad and thereby fine tunes BMP signaling in motor neurons.

scholarly journals Multi-omics integration of methyltransferase-like protein family reveals clinical outcomes and functional signatures in human cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ion John Campeanu ◽  
Yuanyuan Jiang ◽  
Lanxin Liu ◽  
Maksymilian Pilecki ◽  
Alvina Najor ◽  
...  
Keyword(s):  
Human Cancer ◽  
Function Analysis ◽  
Functional Study ◽  
Loss Of Function ◽  
Cancer Cell Growth ◽  
Genomic Amplification ◽  
Growth And Survival ◽  
Protein Levels ◽  
Cellular Processes ◽  
Associated Proteins

AbstractHuman methyltransferase-like (METTL) proteins transfer methyl groups to nucleic acids, proteins, lipids, and other small molecules, subsequently playing important roles in various cellular processes. In this study, we performed integrated genomic, transcriptomic, proteomic, and clinicopathological analyses of 34 METTLs in a large cohort of primary tumor and cell line data. We identified a subset of METTL genes, notably METTL1, METTL7B, and NTMT1, with high frequencies of genomic amplification and/or up-regulation at both the mRNA and protein levels in a spectrum of human cancers. Higher METTL1 expression was associated with high-grade tumors and poor disease prognosis. Loss-of-function analysis in tumor cell lines indicated the biological importance of METTL1, an m7G methyltransferase, in cancer cell growth and survival. Furthermore, functional annotation and pathway analysis of METTL1-associated proteins revealed that, in addition to the METTL1 cofactor WDR4, RNA regulators and DNA packaging complexes may be functionally interconnected with METTL1 in human cancer. Finally, we generated a crystal structure model of the METTL1–WDR4 heterodimeric complex that might aid in understanding the key functional residues. Our results provide new information for further functional study of some METTL alterations in human cancer and might lead to the development of small inhibitors that target cancer-promoting METTLs.

scholarly journals Bioinformatic analysis of methyltransferase-like protein family reveals clinical and functional outcomes in human cancer

2021 ◽  
Author(s):  
Ion Campeanu ◽  
Yuanyuan Jiang ◽  
lanxin Liu ◽  
Maksymilian Pilecki ◽  
Alvina Najor ◽  
...  
Keyword(s):  
Human Cancer ◽  
Function Analysis ◽  
Bioinformatic Analysis ◽  
Loss Of Function ◽  
Cancer Cell Growth ◽  
Genomic Amplification ◽  
Growth And Survival ◽  
Protein Levels ◽  
Cellular Processes ◽  
Associated Proteins

Abstract Human methyltransferase-like (METTL) proteins transfer methyl groups to nucleic acids, proteins, lipids, and other small molecules, subsequently playing important roles in various cellular processes. In this study, we performed integrated genomic, transcriptomic, proteomic, and clinicopathological analyses of 34 METLLs in a large cohort of primary tumor and cell line data. We identified a subset of METTL genes, notably METTL1, METTL7B, and NTMT1, with high frequencies of genomic amplification and/or up-regulation at both the mRNA and protein levels in a spectrum of human cancers. Higher METTL1 expression was associated with high-grade tumors and poor disease prognosis. Loss-of-function analysis in tumor cell lines indicated the biological importance of METTL1, an m7G methyltransferase, in cancer cell growth and survival. Furthermore, functional annotation and pathway analysis of METTL1-associated proteins revealed that, in addition to the METTL1 cofactor WDR4, RNA regulators and DNA packaging complexes may be functionally interconnected with METTL1 in human cancer. Finally, we generated a crystal structure model of the METTL1-WDR4 heterodimeric complex that provides the basis for further development of novel inhibitors. Our results provide a framework for further study of the functional consequences of METTL alterations in human cancer and for development of small inhibitors that target cancer-promoting METTLs.

E3 ubiquitin ligases

2005 ◽  
Vol 41 ◽  
pp. 15-30 ◽  
Author(s):  
Helen C. Ardley ◽  
Philip A. Robinson
Keyword(s):  
Protein Complexes ◽  
Loss Of Function ◽  
Direct Role ◽  
Cellular Processes ◽  
Substrate Protein ◽  
Protein Ubiquitination ◽  
C Terminus ◽  
Full Complement ◽  
Spatio Temporal ◽  
Eukaryotic Organisms

The selectivity of the ubiquitin–26 S proteasome system (UPS) for a particular substrate protein relies on the interaction between a ubiquitin-conjugating enzyme (E2, of which a cell contains relatively few) and a ubiquitin–protein ligase (E3, of which there are possibly hundreds). Post-translational modifications of the protein substrate, such as phosphorylation or hydroxylation, are often required prior to its selection. In this way, the precise spatio-temporal targeting and degradation of a given substrate can be achieved. The E3s are a large, diverse group of proteins, characterized by one of several defining motifs. These include a HECT (homologous to E6-associated protein C-terminus), RING (really interesting new gene) or U-box (a modified RING motif without the full complement of Zn2+-binding ligands) domain. Whereas HECT E3s have a direct role in catalysis during ubiquitination, RING and U-box E3s facilitate protein ubiquitination. These latter two E3 types act as adaptor-like molecules. They bring an E2 and a substrate into sufficiently close proximity to promote the substrate's ubiquitination. Although many RING-type E3s, such as MDM2 (murine double minute clone 2 oncoprotein) and c-Cbl, can apparently act alone, others are found as components of much larger multi-protein complexes, such as the anaphase-promoting complex. Taken together, these multifaceted properties and interactions enable E3s to provide a powerful, and specific, mechanism for protein clearance within all cells of eukaryotic organisms. The importance of E3s is highlighted by the number of normal cellular processes they regulate, and the number of diseases associated with their loss of function or inappropriate targeting.

Metallic prions

2004 ◽  
Vol 71 ◽  
pp. 193-202 ◽  
Author(s):  
David R Brown
Keyword(s):  
Prion Protein ◽  
Binding Capacity ◽  
Normal Function ◽  
Transmissible Spongiform Encephalopathies ◽  
Published Data ◽  
Normal Brain ◽  
Copper Binding ◽  
Loss Of Function ◽  
Spongiform Encephalopathies ◽  
The Brain

Prion diseases, also referred to as transmissible spongiform encephalopathies, are characterized by the deposition of an abnormal isoform of the prion protein in the brain. However, this aggregated, fibrillar, amyloid protein, termed PrPSc, is an altered conformer of a normal brain glycoprotein, PrPc. Understanding the nature of the normal cellular isoform of the prion protein is considered essential to understanding the conversion process that generates PrPSc. To this end much work has focused on elucidation of the normal function and activity of PrPc. Substantial evidence supports the notion that PrPc is a copper-binding protein. In conversion to the abnormal isoform, this Cu-binding activity is lost. Instead, there are some suggestions that the protein might bind other metals such as Mn or Zn. PrPc functions currently under investigation include the possibility that the protein is involved in signal transduction, cell adhesion, Cu transport and resistance to oxidative stress. Of these possibilities, only a role in Cu transport and its action as an antioxidant take into consideration PrPc's Cu-binding capacity. There are also more published data supporting these two functions. There is strong evidence that during the course of prion disease, there is a loss of function of the prion protein. This manifests as a change in metal balance in the brain and other organs and substantial oxidative damage throughout the brain. Thus prions and metals have become tightly linked in the quest to understand the nature of transmissible spongiform encephalopathies.

Co-Culture of ES Cell-Derived Motor Neurons and Myotubes Show the Formation of Neuromuscular Junctions and Changes in Gene Expression

2006 ◽  
Vol 22 (06) ◽  
Author(s):  
Aleid Ruijs ◽  
Tateki Kubo ◽  
Jae Song ◽  
Milan Ranka ◽  
Mark Randolph ◽  
...  
Keyword(s):  
Gene Expression ◽  
Motor Neurons ◽  
Neuromuscular Junctions ◽  
Es Cell

Implications of Fibroblast Growth Factors (FGFs) in Cancer: From Prognostic to Therapeutic Applications

2019 ◽  
Vol 20 (8) ◽  
pp. 852-870
Author(s):  
Hassan Dianat-Moghadam ◽  
Ladan Teimoori-Toolabi
Keyword(s):  
Growth Factors ◽  
Wound Repair ◽  
Fibroblast Growth Factors ◽  
Predictive Biomarkers ◽  
Fibroblast Growth ◽  
Loss Of Function ◽  
Cellular Processes ◽  
Fgfr Signaling ◽  
Proliferation And Metastasis ◽  
Immense Potential

Fibroblast growth factors (FGFs) are pleiotropic molecules exerting autocrine, intracrine and paracrine functions via activating four tyrosine kinase FGF receptors (FGFR), which further trigger a variety of cellular processes including angiogenesis, evasion from apoptosis, bone formation, embryogenesis, wound repair and homeostasis. Four major mechanisms including angiogenesis, inflammation, cell proliferation, and metastasis are active in FGF/FGFR-driven tumors. Furthermore, gain-of-function or loss-of-function in FGFRs1-4 which is due to amplification, fusions, mutations, and changes in tumor–stromal cells interactions, is associated with the development and progression of cancer. Although, the developed small molecule or antibodies targeting FGFR signaling offer immense potential for cancer therapy, emergence of drug resistance, activation of compensatory pathways and systemic toxicity of modulators are bottlenecks in clinical application of anti-FGFRs. In this review, we present FGF/FGFR structure and the mechanisms of its function, as well as cross-talks with other nodes and/or signaling pathways. We describe deregulation of FGF/FGFR-related mechanisms in human disease and tumor progression leading to the presentation of emerging therapeutic approaches, resistance to FGFR targeting, and clinical potentials of individual FGF family in several human cancers. Additionally, the underlying biological mechanisms of FGF/FGFR signaling, besides several attempts to develop predictive biomarkers and combination therapies for different cancers have been explored.

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