scholarly journals TMEM98 is a negative regulator of FRAT mediated Wnt/β-catenin signalling

2019 ◽  
Author(s):  
Tanne van der Wal ◽  
Jan-Paul Lambooij ◽  
Renée van Amerongen
Keyword(s):  
Intracellular Trafficking ◽  
Transmembrane Protein ◽  
Negative Regulator ◽  
Postnatal Life ◽  
Protein Levels ◽  
The Core ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation ◽  
The Many ◽  
Precise Role

SummaryWnt/β-catenin signalling is crucial for maintaining the balance between cell proliferation and differentiation, both during tissue morphogenesis and during tissue maintenance in postnatal life. Whereas the signalling activities of the core Wnt/β-catenin pathway components are understood in great detail, far less is known about the precise role and regulation of the many different modulators of Wnt/β-catenin signalling that have been identified to date.Here we describe TMEM98, a putative transmembrane protein of unknown function, as an interaction partner and regulator of the GSK3-binding protein FRAT2. We show that TMEM98 reduces FRAT2 protein levels and, accordingly, inhibits the FRAT2-mediated induction of β-catenin/TCF signalling. We also characterize the intracellular trafficking of TMEM98 in more detail and show that it is recycled between the plasma membrane and the Golgi. Together, our findings not only reveal a new layer of regulation for Wnt/β-catenin signalling, but also a new biological activity for TMEM98.

Gli2, but notGli1, is required for initial Shh signaling and ectopic activation of the Shh pathway

Development ◽  
2002 ◽  
Vol 129 (20) ◽  
pp. 4753-4761 ◽  
Author(s):  
C. Brian Bai ◽  
Wojtek Auerbach ◽  
Joon S. Lee ◽  
Daniel Stephen ◽  
Alexandra L. Joyner
Keyword(s):  
Signaling Pathway ◽  
Negative Regulator ◽  
Embryonic Patterning ◽  
Mouse Development ◽  
Shh Signaling ◽  
Shh Pathway ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation ◽  
Mammalian Tissues ◽  
Ectopic Activation

The Shh signaling pathway is required in many mammalian tissues for embryonic patterning, cell proliferation and differentiation. In addition, inappropriate activation of the pathway has been implicated in many human tumors. Based on transfection assays and gain-of-function studies in frog and mouse, the transcription factor Gli1 has been proposed to be a major mediator of Shh signaling. To address whether this is the case in mouse, we generated a Gli1 null allele expressing lacZ. Strikingly, Gli1 is not required for mouse development or viability. Of relevance, we show that all transcription of Gli1 in the nervous system and limbs is dependent on Shh and, consequently, Gli1 protein is normally not present to transduce initial Shh signaling. To determine whether Gli1 contributes to the defects seen when the Shh pathway is inappropriately activated and Gli1 transcription is induced, Gli1;Ptc double mutants were generated. We show that Gli1 is not required for the ectopic activation of the Shh signaling pathway or to the early embryonic lethal phenotype in Ptc null mutants. Of significance, we found instead that Gli2 is required for mediating some of the inappropriate Shh signaling in Ptc mutants. Our studies demonstrate that, in mammals, Gli1 is not required for Shh signaling and that Gli2 mediates inappropriate activation of the pathway due to loss of the negative regulator Ptc.

scholarly journals Issues About the Physiological Functions of Prolyl Oligopeptidase Based on Its Discordant Spatial Association With Substrates and Inconsistencies Among mRNA, Protein Levels, and Enzymatic Activity

2009 ◽  
Vol 57 (9) ◽  
pp. 831-848 ◽  
Author(s):  
Timo T. Myöhänen ◽  
J. Arturo García-Horsman ◽  
Jofre Tenorio-Laranga ◽  
Pekka T. Männistö
Keyword(s):  
Spatial Association ◽  
Physiological Role ◽  
Prolyl Oligopeptidase ◽  
Protein Levels ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation ◽  
The Central Nervous System ◽  
Basic Studies ◽  
Catalytic Functions

Prolyl oligopeptidase (POP) is a serine endopeptidase that hydrolyses proline-containing peptides shorter than 30 amino acids. POP may be associated with cognitive functions, possibly via the cleavage of neuropeptides. Recent studies have also suggested novel non-hydrolytic and non-catalytic functions for POP. Moreover, POP has also been proposed as a regulator of inositol 1,4,5-triphosphate signaling and several other functions such as cell proliferation and differentiation, as well as signal transduction in the central nervous system, and it is suspected to be involved in pathological conditions such as Parkinson's and Alzheimer's diseases and cancer. POP inhibitors have been developed to restore the depleted neuropeptide levels encountered in aging or in neurodegenerative disorders. These compounds have shown some antiamnesic effects in animal models. However, the mechanisms of these hypothesized actions are still far from clear. Moreover, the physiological role of POP has remained unknown, and a lack of basic studies, including its distribution, is obvious. The aim of this review is to gather information about POP and to propose some novel roles for this enzyme based on its distribution and its discordant spatial association with its best known substrates.

scholarly journals JNK1 Induces Notch1 Expression to Regulate Genes Governing Photoreceptor Production

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 970
Author(s):  
Pan ◽  
Hu ◽  
Wang ◽  
Zhou ◽  
Zhang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Transcriptional Factor ◽  
Negative Regulator ◽  
Potential Candidate ◽  
Wild Type ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation ◽  
Factor Expression ◽  
Ophthalmic Diseases ◽  
Essential Function

c-Jun N-terminal kinases (JNKs) regulate cell proliferation and differentiation via phosphorylating such transcription factors as c-Jun. The function of JNKs in retinogenesis remains to be elucidated. Here, we report that knocking out Jnk1, but not Jnk2, increased the number of photoreceptors, thus enhancing the electroretinogram (ERG) responses. Intriguingly, Notch1, a well-established negative regulator of photoreceptor genesis, was significantly attenuated in Jnk1 knockout (KO) mice compared to wild-type mice. Mechanistically, light specifically activated JNK1 to phosphorylate c-Jun, which in turn induced Notch1 transcription. The identified JNK1–c-Jun–Notch1 axis strongly inhibited photoreceptor-related transcriptional factor expression and ultimately impaired photoreceptor opsin expression. Our study uncovered an essential function of JNK1 in retinogenesis, revealing JNK1 as a potential candidate for targeting ophthalmic diseases.

scholarly journals Structural basis of SUFU–GLI interaction in human Hedgehog signalling regulation

2013 ◽  
Vol 69 (12) ◽  
pp. 2563-2579 ◽  
Author(s):  
Amy L. Cherry ◽  
Csaba Finta ◽  
Mikael Karlström ◽  
Qianren Jin ◽  
Thomas Schwend ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Negative Regulator ◽  
Structural Basis ◽  
Hedgehog Signalling ◽  
Intrinsically Disordered ◽  
X Ray Scattering ◽  
Cell Proliferation And Differentiation ◽  
Pathway Activation ◽  
Proliferation And Differentiation ◽  
Disordered Loop

Hedgehog signalling plays a fundamental role in the control of metazoan development, cell proliferation and differentiation, as highlighted by the fact that its deregulation is associated with the development of many human tumours. SUFU is an essential intracellular negative regulator of mammalian Hedgehog signalling and acts by binding and modulating the activity of GLI transcription factors. Despite its central importance, little is known about SUFU regulation and the nature of SUFU–GLI interaction. Here, the crystal and small-angle X-ray scattering structures of full-length human SUFU and its complex with the key SYGHL motif conserved in all GLIs are reported. It is demonstrated that GLI binding is associated with major conformational changes in SUFU, including an intrinsically disordered loop that is also crucial for pathway activation. These findings reveal the structure of the SUFU–GLI interface and suggest a mechanism for an essential regulatory step in Hedgehog signalling, offering possibilities for the development of novel pathway modulators and therapeutics.

scholarly journals Differential regulation of the retinoblastoma family of proteins during cell proliferation and differentiation

1998 ◽  
Vol 333 (3) ◽  
pp. 645-654 ◽  
Author(s):  
Judit GARRIGA ◽  
Ana LIMÓN ◽  
Xavier MAYOL ◽  
Sushil G. RANE ◽  
Jeffrey H. ALBRECHT ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Protein Expression ◽  
Cultured Cells ◽  
Protein Levels ◽  
Pocket Protein ◽  
Cell Proliferation And Differentiation ◽  
Mouse Tissues ◽  
Proliferation And Differentiation

In the present study we have analysed the regulation of pocket protein expression and post-transcriptional modifications on cell proliferation and differentiation, both in vivo and in vitro. There are marked changes in pocket protein levels during these transitions, the most striking differences being observed between p130 and p107. The mechanisms responsible for regulating pocket protein levels seem to be dependent on both cell type and pocket protein, in addition to their dependence on the cell growth status. Changes in retinoblastoma protein and p107 levels are independent of their state of phosphorylation. However, whereas p130 phosphorylation to forms characteristic of quiescent/differentiated cells results in the accumulation of p130 protein, phosphorylation of p130 to one or more forms characteristic of cycling cells is accompanied by down-regulation of its protein levels. We also show here that the phosphorylation status and protein levels of p130 and p107 are regulated in vivo as in cultured cells. In vivo, changes in p130 forms are correlated with changes in E2F complexes. Moreover, the modulation of p130 and p107 status during cell differentiation in vitro is consistent with the patterns of protein expression and phosphorylation status found in mouse tissues. Thus in addition to the direct disruption of pocket protein/E2F complexes induced by cyclin/cyclin-dependent kinase, the results we report here indicate that the differential modulation of pocket protein levels constitutes a major mechanism that regulates the pool of each pocket protein that is accessible to E2F and/or other transcription factors.

scholarly journals Interleukin-17 Receptor D in Physiology, Inflammation and Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Charlotte Girondel ◽  
Sylvain Meloche
Keyword(s):  
Cell Biology ◽  
Tumor Formation ◽  
Negative Regulator ◽  
Interleukin 17 ◽  
Lineage Specification ◽  
Tyrosine Kinase Signaling ◽  
Cell Proliferation And Differentiation ◽  
Evolutionarily Conserved ◽  
Proliferation And Differentiation ◽  
Receptor Family

Interleukin-17 receptor D (IL-17RD) is an evolutionarily conserved member of the IL-17 receptor family. Originally identified as a negative regulator of fibroblast growth factor (FGF) signaling under the name of Sef (Similar expression to FGF genes), IL-17RD was subsequently reported to regulate other receptor tyrosine kinase signaling pathways. In addition, recent studies have shown that IL-17RD also modulates IL-17 and Toll-like receptor (TLR) signaling. Combined genetic and cell biology studies have implicated IL-17RD in the control of cell proliferation and differentiation, cell survival, lineage specification, and inflammation. Accumulating evidence also suggest a role for IL-17RD in tumorigenesis. Expression of IL-17RD is down-regulated in various human cancers and recent work has shown that loss of IL-17RD promotes tumor formation in mice. However, the exact mechanisms underlying the tumor suppressor function of IL-17RD remain unclear and some studies have proposed that IL-17RD may exert pro-tumorigenic effects in certain contexts. Here, we provide an overview of the signaling functions of IL-17RD and review the evidence for its involvement in cancer.

NF-Y cooperates with USF1/2 to induce the hematopoietic expression of HOXB4

Blood ◽  
2003 ◽  
Vol 102 (7) ◽  
pp. 2420-2427 ◽  
Author(s):  
Jiang Zhu ◽  
Diane M. Giannola ◽  
Yi Zhang ◽  
Adam J. Rivera ◽  
Stephen G. Emerson
Keyword(s):  
Hematopoietic Cells ◽  
Developmentally Regulated ◽  
Protein Levels ◽  
Nuclear Factor Y ◽  
Cell Proliferation And Differentiation ◽  
Dna Binding Sites ◽  
Primitive Hematopoiesis ◽  
Proliferation And Differentiation ◽  
E Box ◽  
Regulatory Complex

Abstract The transcription factor homeobox B4 (HOXB4) is preferentially expressed in immature hematopoietic cells and implicated in the transition from primitive hematopoiesis to definitive hematopoiesis as well as in immature hematopoietic cell proliferation and differentiation. We previously identified Hox response element 1 (HxRE-1) and HxRE-2/E-box as 2 critical DNA-binding sites of the HOXB4 promoter active in hematopoietic cells and demonstrated that upstream stimulating factor 1 and 2 (USF1/2) activate HOXB4 transcription through their binding to the E-box site. Here we report that the trimeric regulatory complex nuclear factor Y (NF-Y) is the factor that recognizes HxRE-1 and activates the HOXB4 promoter in hematopoietic cells. We further show that NF-Y interacts biochemically with USF1/2 on the HOXB4 promoter, and that the formation of this NF-Y/USF1/2 complex is required for the full activity of the HOXB4 promoter. Most important, NF-Ya subunit protein levels are found to be lower in c-Kit-Gr-1+ granulocytic bone marrow (BM) cells than in c-Kit+ immature BM cells, in parallel with a reduction of NF-Y occupancy on the HOXB4 promoter as shown by chromatin immunoprecipitation (ChIP) assay. These results suggest that NF-Y is a developmentally regulated inducer of the HOXB4 gene in hematopoietic cells. (Blood. 2003;102:2420-2427)

Role of melatonin in regulating neurogenesis: Implications for the neurodegenerative pathology and analogous therapeutics for Alzheimer’s disease

2020 ◽  
Vol 3 (2) ◽  
pp. 216-242 ◽  
Author(s):  
Mayuri Shukla ◽  
Areechun Sotthibundhu ◽  
Piyarat Govitrapong
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Adult Neurogenesis ◽  
Adult Brain ◽  
Therapeutic Approaches ◽  
Therapeutic Implications ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation ◽  
Progenitor Cell Proliferation

The revelation of adult brain exhibiting neurogenesis has established that the brain possesses great plasticity and that neurons could be spawned in the neurogenic zones where hippocampal adult neurogenesis attributes to learning and memory processes. With strong implications in brain functional homeostasis, aging and cognition, various aspects of adult neurogenesis reveal exuberant mechanistic associations thereby further aiding in facilitating the therapeutic approaches regarding the development of neurodegenerative processes in Alzheimer’s Disease (AD). Impaired neurogenesis has been significantly evident in AD with compromised hippocampal function and cognitive deficits. Melatonin the pineal indolamine augments neurogenesis and has been linked to AD development as its levels are compromised with disease progression. Here, in this review, we discuss and appraise the mechanisms via which melatonin regulates neurogenesis in pathophysiological conditions which would unravel the molecular basis in such conditions and its role in endogenous brain repair. Also, its components as key regulators of neural stem and progenitor cell proliferation and differentiation in the embryonic and adult brain would aid in accentuating the therapeutic implications of this indoleamine in line of prevention and treatment of AD.   

Computing Cores for Existential Rules with the Standard Chase and ASP

2020 ◽  
Author(s):  
Markus Krötzsch
Keyword(s):  
Large Class ◽  
Data Exchange ◽  
Answer Set Programming ◽  
Query Answering ◽  
Universal Model ◽  
The Core ◽  
Universal Models ◽  
General Terms ◽  
Special Cases ◽  
The Many

To reason with existential rules (a.k.a. tuple-generating dependencies), one often computes universal models. Among the many such models of different structure and cardinality, the core is arguably the “best”. Especially for finitely satisfiable theories, where the core is the unique smallest universal model, it has advantages in query answering, non-monotonic reasoning, and data exchange. Unfortunately, computing cores is difficult and not supported by most reasoners. We therefore propose ways of computing cores using practically implemented methods from rule reasoning and answer set programming. Our focus is on cases where the standard chase algorithm produces a core. We characterise this desirable situation in general terms that apply to a large class of cores, derive concrete approaches for decidable special cases, and generalise these approaches to non-monotonic extensions of existential rules.

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