bims-dicesi Biomed News
on Diversification of cell signalling
Issue of 2024–12–01
fourteen papers selected by
Ashanika Karandawela
  1. Structural Basis for Chemerin Recognition and Signaling Through Its Receptors.
  2. Exploring Bias in GPCR Signaling and its Implication in Drug Development: A One-Sided Affair.
  3. The Synergy between Topography and Lipid Domains in the Plasma Membrane of Mast Cells Controls the Localization of Signaling Proteins and Facilitates their Coordinated Activation.
  4. Design of allosteric modulators that change GPCR G protein subtype selectivity.
  5. The cell adhesion molecule CD44 acts as a modulator of 5-HT7 receptor functions.
  6. Signal profiles and spatial regulation of β-arrestin recruitment through Gβ5 and GRK3 at the μ-opioid receptor.
  7. Ubiquitin and Ubiquitin-Like Modifications in Organelle Stress Signaling: Ub, Ub, Ub, Ub, Stayin' Alive, Stayin' Alive.
  8. Unraveling GPCRs Allosteric Modulation. Cannabinoid 1 Receptor as a Case Study.
  9. Red and far-red cleavable fluorescent dyes for self-labelling enzyme protein tagging and interrogation of GPCR co-internalization.
  10. Biological Importance of Complex Sphingolipids and Their Structural Diversity in Budding Yeast Saccharomyces cerevisiae.
  11. Megalin: A Sidekick or Nemesis of the Kidney?
  12. Perforation of the host cell plasma membrane during Toxoplasma gondii invasion requires rhoptry exocytosis.
  13. The Jag2/Notch1 signaling axis promotes sebaceous gland differentiation and controls progenitor proliferation.
  14. Thyroid Hormone Action by Genomic and Nongenomic Molecular Mechanisms.
  1. Biomedicines. 2024 Oct 28. pii: 2470. [Epub ahead of print]12(11):
    Structural Basis for Chemerin Recognition and Signaling Through Its Receptors.
    Yezhou Liu, Aijun Liu, Richard D Ye.
      Chemerin is a chemotactic adipokine that participates in a multitude of physiological processes, including adipogenesis, leukocyte chemotaxis, and neuroinflammation. Chemerin exerts biological functions through binding to one or more of its G protein-coupled receptors (GPCRs), namely chemokine-like receptor 1 (CMKLR1), G protein-coupled receptor 1 (GPR1), and CC-motif receptor-like 2 (CCRL2). Of these receptors, CMKLR1 and GPR1 have been confirmed as signaling receptors of chemerin, whereas CCRL2 serves as a chemerin-binding protein without transmembrane signaling. High-resolution structures of two chemerin receptors are now available thanks to recent advancements in structure biology. This review focuses on the structural perspectives of the chemerin receptors with an emphasis on the structure-activity correlation, including key components of the two receptors for ligand recognition and conformational changes induced by chemerin and its derivative peptides for G protein activation. There are also comparisons between the two chemerin receptors and selected GPCRs with peptide ligands for better appreciation of the shared and distinct features of the chemerin receptors in ligand recognition and transmembrane signaling, and in the evolution of this subclass of GPCRs.
    Keywords:  CMKLR1; GPCR structures; GPR1; adipokines; chemerin
    DOI:  https://doi.org/10.3390/biomedicines12112470
  2. Biochemistry. 2024 Nov 29.
    Exploring Bias in GPCR Signaling and its Implication in Drug Development: A One-Sided Affair.
    Madhurjya Protim Borah, Deepika Trakroo, Neeraj Soni, Punita Kumari, Mithu Baidya.
      G protein-coupled receptors (GPCRs) play a pivotal role in regulating numerous physiological processes through their interactions with two key effectors: G proteins and β-arrestins (βarrs). This makes them crucial targets for therapeutic drug development. Interestingly, the evolving concept of biased signaling where ligands selectively activate either the G proteins or the βarrs has not only refined our understanding of segregation of physiological responses downstream of GPCRs but has also revolutionized drug discovery, offering the potential for treatments with enhanced efficacy and minimal side effects. This Review explores the mechanisms behind biased agonism, exploring it through various lenses, including ligand, receptor, cellular systems, location, and tissue-specific biases. It also offers structural insights into both orthosteric and allosteric ligand-binding pockets, structural rearrangements associated with the loops, and how ligand-engineering can contribute to biased signaling. Moreover, we also discuss the unique conformational signature in an intrinsically biased GPCR, which currently remains relatively less explored and adds a new dimension in biased signaling. Lastly, we address the translational challenges and practical considerations in characterizing bias, emphasizing its therapeutic potential and the latest advancements in drug development. By designing ligands that target specific signaling pathways, biased signaling presents a transformative approach to creating safer and more effective therapies. This Review focuses on our current understanding of GPCR-biased signaling, discussing potential mechanisms that lead to bias, the effect of bias on GPCR structures at a molecular level, recent advancements, and its profound potential to drive innovation in drug discovery.
    Keywords:  G protein-coupled receptor; biased agonism; biased signaling; therapeutic drug development
    DOI:  https://doi.org/10.1021/acs.biochem.4c00676
  3. bioRxiv. 2024 Nov 22. pii: 2024.11.22.624791. [Epub ahead of print]
    The Synergy between Topography and Lipid Domains in the Plasma Membrane of Mast Cells Controls the Localization of Signaling Proteins and Facilitates their Coordinated Activation.
    Shirsendu Ghosh, Alice Wagenknecht-Wiesner, Shriya Desai, Jada Vyphuis, Mariena Silvestry Ramos, John L Grazul, Barbara A Baird.
      Similar to T cells and B cells, mast cell surfaces are dominated by microvilli, and like these other immune cells we showed with microvillar cartography (MC) that key signaling proteins for RBL mast cells localize to these topographical features. Although stabilization of ordered lipid nanodomains around antigen-crosslinked IgE-FcεRI is known to facilitate necessary coupling with Lyn tyrosine kinase to initiate transmembrane signaling in these mast cells, the relationship of ordered-lipid nanodomains to membrane topography had not been determined. With nanoscale resolution provided by MC, SEM and co-localization probability (CP) analysis, we found that FcεRI and Lyn kinase are positioned exclusively on the microvilli of resting mast cells in separate nano-assemblies, and upon antigen-activation they merge into overlapping populations together with the LAT scaffold protein, accompanied by elongation and merger of microvilli into ridge-like ruffles. With selective lipid probes, we further found that ordered-lipid nanodomains preferentially occupy microvillar membranes, contrasting with localization of disordered lipids to flatter regions. With this proximity of signaling proteins and ordered lipid nanodomains in microvilli, the mast cells are poised to respond sensitively and efficiently to antigen but only in the presence of this stimulus. Use of a short chain ceramide to disrupt ordered-lipid regions of the plasma membrane and evaluation with MC, CP, and flow cytometry provided strong evidence that the microvillar selective localization of signaling proteins and lipid environments is facilitated by the interplay between ordered-lipid nanodomains and actin attachment proteins, ERM (ezrin, radixin, moesin) and cofilin.
    Significance Statement: Participation of ordered-lipid nanodomains (colloquially dubbed "rafts") to target and regulate immune signaling in the plasma membrane is well documented. Recent studies also demonstrated the role of membrane topography, specifically microvilli, in T-cell and B-cell immune signaling. Here, we show how these features are coordinated in RBL mast cells, a well-established model for mast cells involved in multiple antigen-activated immune responses that include allergies and inflammation mediated by IgE-receptors (IgE-FcεRI). We found that the receptors and a key signaling kinase, together with ordered-lipid nanodomains localize to microvilli in resting cells, forming separated nano-assemblies. Antigen-activation causes elongation and merger of microvilli into ruffles where receptors and kinase coalesce to initiate transmembrane signaling. Selective pre-organization of signaling proteins and targeting lipid domains in microvilli facilitates sensitive and efficient responses to antigenic stimulation. Overall, our results demonstrate complex interplay between membrane topography, ordered-lipid nanodomains, and cytoskeleton attachment proteins in controlling mast cell activation.
    DOI:  https://doi.org/10.1101/2024.11.22.624791
  4. bioRxiv. 2024 Nov 21. pii: 2024.11.20.624209. [Epub ahead of print]
    Design of allosteric modulators that change GPCR G protein subtype selectivity.
    Madelyn N Moore, Kelsey L Person, Abigail Alwin, Campbell Krusemark, Noah Foster, Caroline Ray, Asuka Inoue, Michael R Jackson, Michael J Sheedlo, Lawrence S Barak, Ezequiel Marron Fernandez de Velasco, Steven H Olson, Lauren M Slosky.
      G protein-coupled receptors (GPCRs), the largest family of drug targets, can signal through 16 subtypes of Gα proteins. Biased compounds that selectively activate therapy-relevant pathways promise to be safer, more effective medications. The determinants of bias are poorly understood, however, and rationally-designed, G protein-subtype-selective compounds are lacking. Here, using the prototypical class A GPCR neurotensin receptor 1 (NTSR1), we find that small molecules binding the intracellular GPCR-transducer interface change G protein coupling by subtype-specific and predictable mechanisms, enabling rational drug design. We demonstrate that the compound SBI-553 switches NTSR1 G protein preference by acting both as a molecular bumper and a molecular glue. Structurally, SBI-553 occludes G protein binding determinants on NTSR1, promoting association with select G protein subtypes for which an alternative, shallow-binding conformation is energetically favorable. Minor modifications to the SBI-553 scaffold produce allosteric modulators with distinct G protein subtype selectivity profiles. Selectivity profiles are probe-independent, conserved across species, and translate to differences in in vivo activity. These studies demonstrate that G protein selectivity can be tailored with small changes to a single chemical scaffold targeting the receptor-transducer interface and, as this pocket is broadly conserved, present a strategy for pathway-selective drug discovery applicable to the diverse GPCR superfamily.
    DOI:  https://doi.org/10.1101/2024.11.20.624209
  5. Cell Commun Signal. 2024 Nov 23. 22(1): 563
    The cell adhesion molecule CD44 acts as a modulator of 5-HT7 receptor functions.
    Saskia Borsdorf, Andre Zeug, Yuxin Wu, Elena Mitroshina, Maria Vedunova, Supriya A Gaitonde, Michel Bouvier, Michael C Wehr, Josephine Labus, Evgeni Ponimaskin.
       BACKGROUND: Homo- and heteromerization of G protein-coupled receptors (GPCRs) plays an important role in the regulation of receptor functions. Recently, we demonstrated an interaction between the serotonin receptor 7 (5-HT7R), a class A GPCR, and the cell adhesion molecule CD44. However, the functional consequences of this interaction on 5-HT7R-mediated signaling remained enigmatic.
    METHODS: Using a quantitative FRET (Förster resonance energy transfer) approach, we determined the affinities for the formation of homo- and heteromeric complexes of 5-HT7R and CD44. The impact of heteromerization on 5-HT7R-mediated cAMP signaling was assessed using a cAMP responsive luciferase assay and a FRET-based cAMP biosensor under basal conditions as well as upon pharmacological modulation of the 5-HT7R and/or CD44 with specific ligands. We also investigated receptor-mediated G protein activation using BRET (bioluminescence resonance energy transfer)-based biosensors in both, homo- and heteromeric conditions. Finally, we analyzed expression profiles for 5-HT7R and CD44 in the brain during development.
    RESULTS: We found that homo- and heteromerization of the 5-HT7R and CD44 occur at similar extent. Functionally, heteromerization increased 5-HT7R-mediated cAMP production under basal conditions. In contrast, agonist-mediated cAMP production was decreased in the presence of CD44. Mechanistically, this might be explained by increased Gαs and decreased GαoB activation by 5-HT7R/CD44 heteromers. Unexpectedly, treatment of the heteromeric complex with the CD44 ligand hyaluronic acid boosted constitutive 5-HT7R-mediated cAMP signaling and receptor-mediated transcription, suggesting the existence of a transactivation mechanism.
    CONCLUSIONS: Interaction with the hyaluronan receptor CD44 modulates both the constitutive activity of 5-HT7R as well as its agonist-mediated signaling. Heteromerization also results in the transactivation of 5-HT7R-mediated signaling via CD44 ligand.
    Keywords:  Bioluminescence Resonance Energy Transfer (BRET); Fluorescence Resonance Energy Transfer (FRET); G protein-coupled receptor (GPCR); Hyaluronan receptor CD44; Receptor oligomerization; Serotonin receptor 7 (5-HT7R)
    DOI:  https://doi.org/10.1186/s12964-024-01931-0
  6. Eur J Pharmacol. 2024 Nov 21. pii: S0014-2999(24)00841-0. [Epub ahead of print] 177151
    Signal profiles and spatial regulation of β-arrestin recruitment through Gβ5 and GRK3 at the μ-opioid receptor.
    Carlo Marion C Carino, Suzune Hiratsuka, Ryoji Kise, Gaku Nakamura, Kouki Kawakami, Masataka Yanagawa, Asuka Inoue.
      The μ-opioid receptor (MOR) is a G-protein-coupled receptor (GPCR) that mediates both analgesic effects and adverse effects of opioid drugs. Despite extensive efforts to develop a signal-biased drug, drugs with sufficiently reduced side effects have not been established, in part owing to lack of comprehensive signal transducer profiles of MOR. In this study, by profiling the activity of signal transducers including G proteins and GPCR kinases (GRKs), we revealed an unprecedented mechanism of selective GRK3 activation by Gβ5, leading to β-arrestin recruitment. By utilizing multiple genome-edited cell lines and functional assays, we found that oliceridine, an FDA-approved G-protein-biased agonist, selectively activates Gαz- and GRK3-mediated signaling. Notably, among the five Gβ subtypes, only Gβ5 distinguishes GRK3 from GRK2. Using single-molecule imaging, we found that GRK3 is recruited to the plasma membrane upon MOR agonist stimulation by Gβ1 and Gβ5, yet their interaction dynamics with GRK3 and mechanisms of action are different. Furthermore, particle diffusion analysis suggests that Gβ5 is enriched in confined membrane domains, through which GRK3 is recruited to the plasma membrane in a freely diffusible state, thereby allowing GRK3 to efficiently interact with MOR. These findings provide a mechanism by which MOR agonists rely on a specific Gα-Gβ-GRK axis to induce β-arrestin recruitment.
    Keywords:  G protein-coupled receptor; G proteins; GPCR kinase (GRK); Single-molecule analysis; β-arrestin; μ-opioid receptor
    DOI:  https://doi.org/10.1016/j.ejphar.2024.177151
  7. Bioessays. 2024 Nov 26. e202400230
    Ubiquitin and Ubiquitin-Like Modifications in Organelle Stress Signaling: Ub, Ub, Ub, Ub, Stayin' Alive, Stayin' Alive.
    Elodie Lafont, Eric Chevet.
      Due to various intracellular and external cues, cellular organelles are frequently stressed in both physiological and pathological conditions. Sensing these stresses initiates various signaling pathways which may lead to adaptation of the stressed cells or trigger its their death. At the unicellular level, this stress signaling involves a crosstalk between different organelles. At the multicellular level, such pathways can contribute to indicate the presence of a stressed cell to its neighboring cells. Here, we highlight the crucial and diverse roles played by Ubiquitin and Ubiquitin-like modification in organelle stress signaling.
    Keywords:  Ubiquitin; Ubiquitin‐like modifications; adaptation; cell death; cellular stress; organelle
    DOI:  https://doi.org/10.1002/bies.202400230
  8. Proteins. 2024 Nov 25.
    Unraveling GPCRs Allosteric Modulation. Cannabinoid 1 Receptor as a Case Study.
    Alejandro Cruz, Arieh Warshel.
      G-protein-coupled receptors (GPCRs) constitute one of the most prominent families of integral membrane receptor proteins that mediate most transmembrane signaling processes. Malfunction of these signal transduction processes is one of the underlying causes of many human pathologies (Parkinson's, Huntington's, heart diseases, etc), provoking that GPCRs are the largest family of druggable proteins. However, these receptors have been targeted traditionally by orthosteric ligands, which usually causes side effects due to the simultaneous targeting of homologous receptor subtypes. Allosteric modulation offers a promising alternative approach to circumvent this problematic and, thus, comprehending its details is a most important task. Here we use the Cannabinoid type-1 receptor (CB1R) in trying to shed light on this issue, focusing on positive allosteric modulation. This is done by using the protein-dipole Langevin-dipole (PDLD) within the linear response approximation (LRA) framework (PDLD/S-2000) along with our coarse-grained (CG) model of membrane proteins to evaluate the dissociation constants (KBs) and cooperativity factors (αs) for a diverse series of CB1R positive allosteric modulators belonging to the 2-phenylindole structural class, considering CP55940 as an agonist. The agreement with the experimental data evinces that significantly populated allosteric modulator:CB1R and allosteric modulator:CP55940:CB1R complexes have been identified and characterized successfully. Analyzing them, it has been determined that CB1R positive allosteric modulation lies in an outwards displacement of transmembrane α helix (TM) 4 extracellular end and in the regulation of the range of motion of a compound TM7 movement for binary and ternary complexes, respectively. In this respect, we achieved a better comprehension of the molecular architecture of CB1R positive allosteric site, identifying Lys1923.28 and Gly1943.30 as key residues regarding electrostatic interactions inside this cavity, and to rationalize (at both structural and molecular level) the exhibited stereoselectivity in relation to positive allosteric modulation activity by considered CB1R allosteric modulators. Additionally, putative/postulated allosteric binding sites have been screened successfully, identifying the real CB1R positive allosteric site, and most structure-activity relationship (SAR) studies of CB1R 2-phenylindole allosteric modulators have been rationalized. All these findings point out towards the predictive value of the methodology used in the current work, which can be applied to other biophysical systems of interest. The results presented in this study contribute significantly to understand GPCRs allosteric modulation and, hopefully, will encourage a more thorough exploration of the topic.
    Keywords:  GPCRs allosteric modulation; binding free energy calculations; cannabinoid type‐1 receptor; cannabinoid type‐1 receptor positive allosteric modulation; cooperativity factor; dissociation constant; folding free energy calculations
    DOI:  https://doi.org/10.1002/prot.26762
  9. RSC Chem Biol. 2024 Nov 18.
    Red and far-red cleavable fluorescent dyes for self-labelling enzyme protein tagging and interrogation of GPCR co-internalization.
    Kilian Roßmann, Ramona Birke, Joshua Levitz, Ben Jones, Johannes Broichhagen.
      Post-labelling cleavable substrates for self-labelling protein tags, such as SNAP- and Halo-tags, can be used to study cell surface receptor trafficking events by stripping dyes from non-internalized protein pools. Since the complexity of receptor biology requires the use of multiple and orthogonal approaches to simultaneously probe multiple receptor pools, we report the development of four membrane impermeable probes that covalently bind to either the SNAP- or the Halo-tag in the red to far-red range. These molecules bear a disulfide bond to release the non-internalized probe using the reducing agent sodium 2-mercaptoethane sulfonate (MESNA). As such, our approach allows the simultaneous visualization of multiple internalized cell surface proteins in two colors which we showcase using G protein-coupled receptors. We use this approach to detect internalized group II metabotropic glutamate receptor (mGluRs), homo- and heterodimers, and to reveal unidirectional crosstalk between co-expressed glucagon-like peptide 1 (GLP1R) and glucose-dependent insulinotropic polypeptide receptors (GIPR). In these applications, we translate our method to both high resolution imaging and quantitative, high throughput assays, demonstrating the value of our approach for a wide range of applications.
    DOI:  https://doi.org/10.1039/d4cb00209a
  10. Int J Mol Sci. 2024 Nov 19. pii: 12422. [Epub ahead of print]25(22):
    Biological Importance of Complex Sphingolipids and Their Structural Diversity in Budding Yeast Saccharomyces cerevisiae.
    Motohiro Tani.
      Complex sphingolipids are components of eukaryotic biomembranes and are involved in various physiological functions. In addition, their synthetic intermediates and metabolites, such as ceramide, sphingoid long-chain base, and sphingoid long-chain base 1-phosphate, play important roles as signaling molecules that regulate intracellular signal transduction systems. Complex sphingolipids have a large number of structural variations, and this structural diversity is considered an important molecular basis for their various physiological functions. The budding yeast Saccharomyces cerevisiae has simpler structural variations in complex sphingolipids compared to mammals and is, therefore, a useful model organism for elucidating the physiological significance of this structural diversity. In this review, we focus on the structure and function of complex sphingolipids in S. cerevisiae and summarize the response mechanisms of S. cerevisiae to metabolic abnormalities in complex sphingolipids.
    Keywords:  Saccharomyces cerevisiae; budding yeast; ceramide; complex sphingolipid; long-chain base; sphingolipid
    DOI:  https://doi.org/10.3390/ijms252212422
  11. J Am Soc Nephrol. 2024 Nov 15.
    Megalin: A Sidekick or Nemesis of the Kidney?
    Kalyani Kulkarni, Tahir Hussain.
       ABSTRACT: Megalin is an endocytic receptor in the proximal tubules that reabsorbs filtered proteins in the kidneys. Recycling of megalin after endocytosis and its expression on the apical plasma membrane of the proximal tubule are critical for its function. The expression of megalin in the kidney undergoes dynamic changes under physiological and pathophysiological conditions. Receptors and various effector signaling components regulate megalin expression and potentially function. Genetic manipulation and rare mutations in megalin suggest that a lack or deficiency in megalin expression/function promotes tubular proteinuria and albuminuria. However, the role of megalin in kidney diseases associated with obesity, diabetes, hypertension, and nephrotoxicity remains unclear. To address these questions, animal and human studies have indicated megalin as a protective, injurious, and potentially urinary marker of nephropathy. This article reviews the literature on the regulation of megalin expression and the role of megalin in the pathophysiology of the kidney under experimental and clinical conditions. Moreover, this review articulates the need for studies that can clarify whether megalin can serve as a therapeutic target, in one way or the other, to treat kidney disease.
    DOI:  https://doi.org/10.1681/ASN.0000000572
  12. bioRxiv. 2024 Nov 11. pii: 2024.10.12.618018. [Epub ahead of print]
    Perforation of the host cell plasma membrane during Toxoplasma gondii invasion requires rhoptry exocytosis.
    Frances Male, Yuto Kegawa, Paul S Blank, Irene Jiménez-Munguía, Saima M Sidik, Dylan Valleau, Sebastian Lourido, Maryse Lebrun, Joshua Zimmerberg, Gary E Ward.
      Toxoplasma gondii is an obligate intracellular parasite, and the delivery of effector proteins from the parasite into the host cell during invasion is critical for invasion itself and for parasite virulence. The effector proteins are released from specialized apical secretory organelles known as rhoptries. While much has been learned recently about the structure and composition of the rhoptry exocytic machinery and the function of individual rhoptry effector proteins that are exocytosed, virtually nothing is known about how the released proteins are translocated across the host cell plasma membrane. Previous electrophysiology experiments reported an unanticipated observation that invasion by T. gondii is preceded by a transient increase in host cell plasma membrane conductance. Here, we confirm this electrophysiological observation and propose that the conductance transient represents a parasite-induced perforation in the host cell plasma membrane through which rhoptry proteins are delivered. As a first step towards testing this hypothesis, and to provide higher throughput than patch clamp electrophysiology, we developed an alternative assay to detect the perforation. This assay utilizes high-speed, multi-wavelength fluorescence imaging to enable simultaneous visualization of host cell perforation and parasite invasion. Using this assay, we interrogated a panel of mutant parasites conditionally depleted of key invasion-related proteins. Parasites lacking signaling proteins involved in triggering rhoptry secretion ( e.g. , CLAMP) or components of the rhoptry exocytic machinery ( e.g. , Nd9, RASP2) are defective in their ability to induce the perforation. These data are consistent with a model in which the perforating agents that disrupt host cell membrane integrity during invasion - and may thereby provide the conduit for delivery of rhoptry effector proteins - are stored within the rhoptries themselves and released upon contact with the host cell.
    DOI:  https://doi.org/10.1101/2024.10.12.618018
  13. Elife. 2024 Nov 25. pii: RP98747. [Epub ahead of print]13
    The Jag2/Notch1 signaling axis promotes sebaceous gland differentiation and controls progenitor proliferation.
    Syeda Nayab Fatima Abidi, Sara Chan, Kerstin Seidel, Daniel Lafkas, Louis Vermeulen, Frank Peale, Christian W Siebel.
      The sebaceous gland (SG) is a vital appendage of the epidermis, and its normal homeostasis and function is crucial for effective maintenance of the skin barrier. Notch signaling is a well-known regulator of epidermal differentiation, and has also been shown to be involved in postnatal maintenance of SGs. However, the precise role of Notch signaling in regulating SG differentiation in the adult homeostatic skin remains unclear. While there is evidence to suggest that Notch1 is the primary Notch receptor involved in regulating the differentiation process, the ligand remains unknown. Using monoclonal therapeutic antibodies designed to specifically inhibit of each of the Notch ligands or receptors, we have identified the Jag2/Notch1 signaling axis as the primary regulator of sebocyte differentiation in mouse homeostatic skin. Mature sebocytes are lost upon specific inhibition of the Jag2 ligand or Notch1 receptor, resulting in the accumulation of proliferative stem/progenitor cells in the SG. Strikingly, this phenotype is reversible, as these stem/progenitor cells re-enter differentiation when the inhibition of Notch activity is lifted. Thus, Notch activity promotes correct sebocyte differentiation, and is required to restrict progenitor proliferation.
    Keywords:  Notch signaling; cell fates; differentiation; mouse; regenerative medicine; stem cells; therapeutic antibodies
    DOI:  https://doi.org/10.7554/eLife.98747
  14. Methods Mol Biol. 2025 ;2876 17-34
    Thyroid Hormone Action by Genomic and Nongenomic Molecular Mechanisms.
    Ana Aranda.
      The thyroid hormones, thyroxine (T4) and triiodothyronine (T3), are pivotal in regulating various physiological processes including growth, development, and metabolism. The biological actions of thyroid hormones are primarily initiated by binding to nuclear thyroid hormone receptors (TRs). These receptors, belonging to the superfamily of nuclear receptors, act as ligand-dependent transcription factors. Transcriptional regulation by TRs is mediated by the recruitment of coregulators, governing activation and repression of target genes, thereby modulating cellular responses to thyroid hormones. Beyond this canonical genomic pathway, TH can regulate the expression of genes not directly bound by TRs through cross-talk mechanisms with other transcription factors and signaling pathways. Thyroid hormones can also elicit rapid non-genomic effects, potentially mediated by extranuclear TR proteins or by interactions with membrane receptors such as integrin αvβ3. This non-genomic mode of action adds another layer of complexity to the diverse array of physiological responses orchestrated by thyroid hormones, expanding our understanding of their multifaceted actions.
    Keywords:  Integrin αvβ3 membrane receptor; Thyroid hormone receptors (TRs); Thyroid hormone response elements; Thyroid hormones (THs)
    DOI:  https://doi.org/10.1007/978-1-0716-4252-8_2
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