scholarly journals DEPTOR in Skeletal Development and Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Jose Miguel Perez-Tejeiro ◽  
Fabiana Csukasi
Keyword(s):  
Skeletal Development ◽  
Negative Regulator ◽  
Current Understanding ◽  
Skeletal Biology ◽  
Interacting Protein ◽  
Cellular Processes ◽  
The Past ◽  
Mechanistic Target Of Rapamycin ◽  
Evolutionarily Conserved ◽  
Important Regulator

Discovered in 2009, the DEP-domain containing mTOR-interacting protein, DEPTOR, is a known regulator of the mechanistic target of rapamycin (mTOR), an evolutionarily conserved kinase that regulates diverse cellular processes in response to environmental stimuli. DEPTOR was originally identified as a negative regulator of mTOR complexes 1 (mTORC1) and 2 (mTORC2). However, recent discoveries have started to unravel the roles of DEPTOR in mTOR-independent responses. In the past few years, mTOR emerged as an important regulator of skeletal development, growth, and homeostasis; the dysregulation of its activity contributes to the development of several skeletal diseases, both chronic and genetic. Even more recently, several groups have reported on the relevance of DEPTOR in skeletal biology through its action on mTOR-dependent and mTOR-independent pathways. In this review, we summarize the current understanding of DEPTOR in skeletal development and disease.

scholarly journals Arabidopsis ALIX is required for the endosomal localization of the deubiquitinating enzyme AMSH3

2015 ◽  
Vol 112 (40) ◽  
pp. E5543-E5551 ◽  
Author(s):  
Kamila Kalinowska ◽  
Marie-Kristin Nagel ◽  
Kaija Goodman ◽  
Laura Cuyas ◽  
Franziska Anzenberger ◽  
...  
Keyword(s):  
Cellular Level ◽  
Deubiquitinating Enzymes ◽  
Interacting Protein ◽  
Endosomal Sorting ◽  
Cellular Processes ◽  
Late Endosomes ◽  
Knockout Mutants ◽  
Important Regulator

Ubiquitination is a signal for various cellular processes, including for endocytic degradation of plasma membrane cargos. Ubiquitinating as well as deubiquitinating enzymes (DUBs) can regulate these processes by modifying the ubiquitination status of target protein. Although accumulating evidence points to the important regulatory role of DUBs, the molecular basis of their regulation is still not well understood. Associated molecule with the SH3 domain of signal transduction adaptor molecule (STAM) (AMSH) is a conserved metalloprotease DUB in eukaryotes. AMSH proteins interact with components of the endosomal sorting complex required for transport (ESCRT) and are implicated in intracellular trafficking. To investigate how the function of AMSH is regulated at the cellular level, we carried out an interaction screen for the Arabidopsis AMSH proteins and identified the Arabidopsis homolog of apoptosis-linked gene-2 interacting protein X (ALIX) as a protein interacting with AMSH3 in vitro and in vivo. Analysis of alix knockout mutants in Arabidopsis showed that ALIX is essential for plant growth and development and that ALIX is important for the biogenesis of the vacuole and multivesicular bodies (MVBs). Cell biological analysis revealed that ALIX and AMSH3 colocalize on late endosomes. Although ALIX did not stimulate AMSH3 activity in vitro, in the absence of ALIX, AMSH3 localization on endosomes was abolished. Taken together, our data indicate that ALIX could function as an important regulator for AMSH3 function at the late endosomes.

scholarly journals Ras, PI3K and mTORC2 – three's a crowd?

2020 ◽  
Vol 133 (19) ◽  
pp. jcs234930
Author(s):  
Stephen F. Smith ◽  
Shannon E. Collins ◽  
Pascale G. Charest
Keyword(s):  
Ras Signaling ◽  
Cell Type ◽  
Cellular Processes ◽  
Mechanistic Target Of Rapamycin ◽  
Evolutionarily Conserved ◽  
Intracellular Compartments ◽  
Ras Effectors ◽  
And Migration ◽  
The Relationship ◽  
Proliferation And Migration

ABSTRACTThe Ras oncogene is notoriously difficult to target with specific therapeutics. Consequently, there is interest to better understand the Ras signaling pathways to identify potential targetable effectors. Recently, the mechanistic target of rapamycin complex 2 (mTORC2) was identified as an evolutionarily conserved Ras effector. mTORC2 regulates essential cellular processes, including metabolism, survival, growth, proliferation and migration. Moreover, increasing evidence implicate mTORC2 in oncogenesis. Little is known about the regulation of mTORC2 activity, but proposed mechanisms include a role for phosphatidylinositol (3,4,5)-trisphosphate – which is produced by class I phosphatidylinositol 3-kinases (PI3Ks), well-characterized Ras effectors. Therefore, the relationship between Ras, PI3K and mTORC2, in both normal physiology and cancer is unclear; moreover, seemingly conflicting observations have been reported. Here, we review the evidence on potential links between Ras, PI3K and mTORC2. Interestingly, data suggest that Ras and PI3K are both direct regulators of mTORC2 but that they act on distinct pools of mTORC2: Ras activates mTORC2 at the plasma membrane, whereas PI3K activates mTORC2 at intracellular compartments. Consequently, we propose a model to explain how Ras and PI3K can differentially regulate mTORC2, and highlight the diversity in the mechanisms of mTORC2 regulation, which appear to be determined by the stimulus, cell type, and the molecularly and spatially distinct mTORC2 pools.

scholarly journals Novel Roles of Hakai in Cell Proliferation and Oncogenesis

2009 ◽  
Vol 20 (15) ◽  
pp. 3533-3542 ◽  
Author(s):  
Angélica Figueroa ◽  
Hirokazu Kotani ◽  
Yoshinobu Toda ◽  
Krystyna Mazan-Mamczarz ◽  
Eva-Christina Mueller ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Rna Binding ◽  
Tumor Development ◽  
Human Colon ◽  
Dominant Negative ◽  
Interacting Protein ◽  
Cell Contacts ◽  
Cellular Processes ◽  
Important Regulator ◽  
Cell Cell

During tumor development, cells acquire multiple phenotypic changes upon misregulation of oncoproteins and tumor suppressor proteins. Hakai was originally identified as an E3 ubiquitin-ligase for the E-cadherin complex that regulates cell–cell contacts. Here, we present evidence that Hakai plays a crucial role in various cellular processes and tumorigenesis. Overexpression of Hakai affects not only cell–cell contacts but also proliferation in both epithelial and fibroblast cells. Furthermore, the knockdown of Hakai significantly suppresses proliferation of transformed epithelial cells. Expression of Hakai is correlated to the proliferation rate in human tissues and is highly up-regulated in human colon and gastric adenocarcinomas. Moreover, we identify PTB-associated splicing factor (PSF), an RNA-binding protein, as a novel Hakai-interacting protein. By using cDNA arrays, we have determined various specific PSF-associated mRNAs encoding proteins that are involved in several cancer-related processes. Hakai affects the ability of PSF to bind these mRNAs, and expression of PSF short hairpin RNA or a dominant-negative PSF mutant significantly suppresses proliferation of Hakai-overexpressing cells. Collectively, these results suggest that Hakai is an important regulator of cell proliferation and that Hakai may be an oncoprotein and a potential molecular target for cancer treatment.

scholarly journals Uncovering the Invisible: Mono-ADP-ribosylation Moved into the Spotlight

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 680
Author(s):  
Ann-Katrin Hopp ◽  
Michael O. Hottiger
Keyword(s):  
Nucleic Acids ◽  
Nicotinamide Adenine Dinucleotide ◽  
Physiological Function ◽  
Adenosine Diphosphate ◽  
Current Understanding ◽  
Post Translational Modification ◽  
Adp Ribosylation ◽  
Cellular Processes ◽  
The Past ◽  
Technological Advances

Adenosine diphosphate (ADP)-ribosylation is a nicotinamide adenine dinucleotide (NAD+)-dependent post-translational modification that is found on proteins as well as on nucleic acids. While ARTD1/PARP1-mediated poly-ADP-ribosylation has extensively been studied in the past 60 years, comparably little is known about the physiological function of mono-ADP-ribosylation and the enzymes involved in its turnover. Promising technological advances have enabled the development of innovative tools to detect NAD+ and NAD+/NADH (H for hydrogen) ratios as well as ADP-ribosylation. These tools have significantly enhanced our current understanding of how intracellular NAD dynamics contribute to the regulation of ADP-ribosylation as well as to how mono-ADP-ribosylation integrates into various cellular processes. Here, we discuss the recent technological advances, as well as associated new biological findings and concepts.

scholarly journals The PTH/PTHrP-SIK3 pathway affects skeletogenesis through altered mTOR signaling

2018 ◽  
Vol 10 (459) ◽  
pp. eaat9356 ◽  
Author(s):  
Fabiana Csukasi ◽  
Ivan Duran ◽  
Maya Barad ◽  
Tomas Barta ◽  
Iva Gudernova ◽  
...  
Keyword(s):  
Catalytic Domain ◽  
Skeletal Development ◽  
Mtor Signaling ◽  
Negative Regulator ◽  
Common Mechanism ◽  
Homozygous Mutation ◽  
Constitutive Activation ◽  
Mechanistic Target Of Rapamycin ◽  
Pthrp Receptor ◽  
Mtor Complex 1

Studies have suggested a role for the mammalian (or mechanistic) target of rapamycin (mTOR) in skeletal development and homeostasis, yet there is no evidence connecting mTOR with the key signaling pathways that regulate skeletogenesis. We identified a parathyroid hormone (PTH)/PTH-related peptide (PTHrP)–salt-inducible kinase 3 (SIK3)–mTOR signaling cascade essential for skeletogenesis. While investigating a new skeletal dysplasia caused by a homozygous mutation in the catalytic domain of SIK3, we observed decreased activity of mTOR complex 1 (mTORC1) and mTORC2 due to accumulation of DEPTOR, a negative regulator of both mTOR complexes. This SIK3 syndrome shared skeletal features with Jansen metaphyseal chondrodysplasia (JMC), a disorder caused by constitutive activation of the PTH/PTHrP receptor. JMC-derived chondrocytes showed reduced SIK3 activity, elevated DEPTOR, and decreased mTORC1 and mTORC2 activity, indicating a common mechanism of disease. The data demonstrate that SIK3 is an essential positive regulator of mTOR signaling that functions by triggering DEPTOR degradation in response to PTH/PTHrP signaling during skeletogenesis.

miR-125b enhances metastasis and progression of cancer via the TXNIP and HIF1α pathway in pancreatic cancer

2021 ◽  
pp. 1-12
Author(s):  
Pengli Wang ◽  
Dan Zheng ◽  
Hongyang Qi ◽  
Qi Gao
Keyword(s):  
Pancreatic Cancer ◽  
Hypoxia Inducible Factor ◽  
Immunofluorescence Assay ◽  
Luciferase Assay ◽  
Interacting Protein ◽  
Over Expression ◽  
Thioredoxin Interacting Protein ◽  
Cellular Processes ◽  
And Migration

BACKGROUND: MicroRNAs (miRNAs) play potential role in the development of various types of cancer conditions including pancreatic cancer (PC) targeting several cellular processes. Present study was aimed to evaluate function of miR-125b and the mechanism involved in PC. METHODS: Cell migration, MTT and BrdU study was done to establish the migration capability, cell viability and cell proliferation respectively. Binding sites for miR-125b were recognized by luciferase assay, expression of protein by western blot and immunofluorescence assay. In vivo study was done by BALB/c nude xenograft mice for evaluating the function of miR-125b. RESULTS: The study showed that expression of miR-125b was elevated in PC cells and tissues, and was correlated to proliferation and migration of cells. Also, over-expression of miR-125b encouraged migration, metastasis and proliferation of BxPC-3 cells, the suppression reversed it. We also noticed that thioredoxin-interacting protein (TXNIP) was the potential target of miR-125b. The outcomes also suggested that miR-125b governed the expression of TXNIP inversely via directly attaching to the 3′-UTR activating hypoxia-inducible factor 1α (HIF1α). Looking into the relation between HIF1α and TXNIP, we discovered that TXNIP caused the degradation and export of HIF1α by making a complex with it. CONCLUSION: The miR-125b-TXNIP-HIF1α pathway may serve useful strategy for diagnosing and treating PC.

scholarly journals TFEB Signalling-Related MicroRNAs and Autophagy

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 985
Author(s):  
Davide Corà ◽  
Federico Bussolino ◽  
Gabriella Doronzo
Keyword(s):  
Transcriptional Regulation ◽  
Stress Factors ◽  
Cellular Functions ◽  
Post Translational Modifications ◽  
Cellular Processes ◽  
Factor Deficiency ◽  
Transcription Factor Eb ◽  
Important Regulator ◽  
Response To Stress ◽  
Post Transcriptional Regulation

The oncogenic Transcription Factor EB (TFEB), a member of MITF-TFE family, is known to be the most important regulator of the transcription of genes responsible for the control of lysosomal biogenesis and functions, autophagy, and vesicles flux. TFEB activation occurs in response to stress factors such as nutrient and growth factor deficiency, hypoxia, lysosomal stress, and mitochondrial damage. To reach the final functional status, TFEB is regulated in multimodal ways, including transcriptional rate, post-transcriptional regulation, and post-translational modifications. Post-transcriptional regulation is in part mediated by miRNAs. miRNAs have been linked to many cellular processes involved both in physiology and pathology, such as cell migration, proliferation, differentiation, and apoptosis. miRNAs also play a significant role in autophagy, which exerts a crucial role in cell behaviour during stress or survival responses. In particular, several miRNAs directly recognise TFEB transcript or indirectly regulate its function by targeting accessory molecules or enzymes involved in its post-translational modifications. Moreover, the transcriptional programs triggered by TFEB may be influenced by the miRNA-mediated regulation of TFEB targets. Finally, recent important studies indicate that the transcription of many miRNAs is regulated by TFEB itself. In this review, we describe the interplay between miRNAs with TFEB and focus on how these types of crosstalk affect TFEB activation and cellular functions.

scholarly journals CrossTORC and WNTegration in Disease: Focus on Lymphangioleiomyomatosis

2021 ◽  
Vol 22 (5) ◽  
pp. 2233
Author(s):  
Jilly Frances Evans ◽  
Kseniya Obraztsova ◽  
Susan M. Lin ◽  
Vera P. Krymskaya
Keyword(s):  
Integration Site ◽  
Cancer Development ◽  
Mechanistic Target Of Rapamycin ◽  
Complex Interactions ◽  
Signal Transduction Networks ◽  
Evolutionarily Conserved ◽  
Future Potential ◽  
Cellular Development ◽  
Wnt Signal ◽  
Disease Focus

The mechanistic target of rapamycin (mTOR) and wingless-related integration site (Wnt) signal transduction networks are evolutionarily conserved mammalian growth and cellular development networks. Most cells express many of the proteins in both pathways, and this review will briefly describe only the key proteins and their intra- and extracellular crosstalk. These complex interactions will be discussed in relation to cancer development, drug resistance, and stem cell exhaustion. This review will also highlight the tumor-suppressive tuberous sclerosis complex (TSC) mutated, mTOR-hyperactive lung disease of women, lymphangioleiomyomatosis (LAM). We will summarize recent advances in the targeting of these pathways by monotherapy or combination therapy, as well as future potential treatments.

Temporal and spatial expression of adrenomedullin and its receptors in the porcine uterus and peri-implantation conceptuses

2021 ◽  
Author(s):  
Sudikshya Paudel ◽  
Bangmin Liu ◽  
Magdalina J Cummings ◽  
Kelsey E Quinn ◽  
Fuller W Bazer ◽  
...  
Keyword(s):  
Peptide Hormone ◽  
Uterine Receptivity ◽  
Mechanistic Target Of Rapamycin ◽  
Evolutionarily Conserved ◽  
Uterine Fluid ◽  
Temporal And Spatial ◽  
Functional Peptide ◽  
And Migration ◽  
Implantation Period ◽  
Proliferation And Migration

Abstract Adrenomedullin (ADM) is an evolutionarily conserved multi-functional peptide hormone that regulates implantation, embryo spacing and placentation in humans and rodents. However, the potential roles of ADM in implantation and placentation in pigs, as a litter-bearing species, are not known. This study determined abundances of ADM in uterine luminal fluid, and the patterns of expression of ADM and its receptor components (CALCRL, RAMP2, RAMP3, and ACKR3) in uteri from cyclic and pregnant gilts, as well as conceptuses (embryonic/fetus and its extra-embryonic membranes) during the peri-implantation period of pregnancy. Total recoverable ADM was greater in the uterine fluid of pregnant compared with cyclic gilts between Days 10 and 16 post-estrus, and was from uterine luminal epithelial (LE) and conceptus trophectoderm (Tr) cells. Uterine expression of CALCRL, RAMP2, and ACKR3 were affected by day (P < 0.05), pregnant status (P < 0.01) and/or day x status (P < 0.05). Within porcine conceptuses, expression of CALCRL, RAMP2 and ACKR3 increased between Days 10 and 16 of pregnancy. Using an established porcine trophectoderm (pTr1) cell line, it was determined that 10−7 M ADM stimulated proliferation of pTr1 cells (P < 0.05) at 48 h, and increased phosphorylated mechanistic target of rapamycin (p-MTOR) and 4E binding protein 1 (p-4EBP1) by 6.1- and 4.9-fold (P < 0.0001), respectively. These novel results indicate a significant role for ADM in uterine receptivity for implantation and conceptus growth and development in pigs. They also provide a framework for future studies of ADM signaling to affect proliferation and migration of Tr cells, spacing of blastocysts, implantation and placentation in pigs.

The Sox-domain containing geneDichaete/fish-hookacts in concert withvndandindto regulate cell fate in theDrosophilaneuroectoderm

Development ◽  
2002 ◽  
Vol 129 (5) ◽  
pp. 1165-1174 ◽  
Author(s):  
Guoyan Zhao ◽  
James B. Skeath
Keyword(s):  
Cell Fate ◽  
Nerve Cord ◽  
Double Mutant ◽  
Ventral Nerve Cord ◽  
Egf Receptor ◽  
Dorsoventral Axis ◽  
Mutant Analysis ◽  
Evolutionarily Conserved ◽  
Specific Manner ◽  
Important Regulator

In the Drosophila embryonic central nervous system, neural stem cells, called neuroblasts, acquire fates in a position-specific manner. Recent work has identified a set of genes that functions along the dorsoventral axis to enable neuroblasts that develop in different dorsoventral domains to acquire distinct fates. These genes include the evolutionarily conserved transcription factors ventral nerve cord defective and intermediate neuroblasts defective, as well as the Drosophila EGF receptor. We show that the Sox-domain-containing gene Dichaete/fish-hook also plays a crucial role to pattern the neuroectoderm along the DV axis. Dichaete is expressed in the medial and intermediate columns of the neuroectoderm, and mutant analysis indicates that Dichaete regulates cell fate and neuroblast formation in these domains. Molecular epistasis tests, double mutant analysis and dosage-sensitive interactions demonstrate that during these processes, Dichaete functions in parallel with ventral nerve cord defective and intermediate neuroblasts defective, and downstream of EGF receptor signaling to mediate its effect on development. These results identify Dichaete as an important regulator of dorsoventral pattern in the neuroectoderm, and indicate that Dichaete acts in concert with ventral nerve cord defective and intermediate neuroblasts defective to regulate pattern and cell fate in the neuroectoderm.

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