دورية أكاديمية
Affinity-matured DLL4 ligands as broad-spectrum modulators of Notch signaling.
| العنوان: | Affinity-matured DLL4 ligands as broad-spectrum modulators of Notch signaling. |
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| المؤلفون: | Gonzalez-Perez D; Department of Drug Discovery, Moffitt Cancer Center, Tampa, FL, USA., Das S; Department of Immunology, Moffitt Cancer Center, Tampa, FL, USA., Antfolk D; Department of Drug Discovery, Moffitt Cancer Center, Tampa, FL, USA., Ahsan HS; Stanford Institute for Stem Cell Biology & Regenerative Medicine, Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA., Medina E; Department of Drug Discovery, Moffitt Cancer Center, Tampa, FL, USA., Dundes CE; Stanford Institute for Stem Cell Biology & Regenerative Medicine, Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA., Jokhai RT; Stanford Institute for Stem Cell Biology & Regenerative Medicine, Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA., Egan ED; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA., Blacklow SC; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.; Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, USA., Loh KM; Stanford Institute for Stem Cell Biology & Regenerative Medicine, Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA., Rodriguez PC; Department of Immunology, Moffitt Cancer Center, Tampa, FL, USA., Luca VC; Department of Drug Discovery, Moffitt Cancer Center, Tampa, FL, USA. vince.luca@moffitt.org. |
| المصدر: | Nature chemical biology [Nat Chem Biol] 2023 Jan; Vol. 19 (1), pp. 9-17. Date of Electronic Publication: 2022 Sep 01. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Nature Pub. Group Country of Publication: United States NLM ID: 101231976 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1552-4469 (Electronic) Linking ISSN: 15524450 NLM ISO Abbreviation: Nat Chem Biol Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: New York, NY : Nature Pub. Group, [2005]- |
| مواضيع طبية MeSH: | Adaptor Proteins, Signal Transducing*/metabolism , Intercellular Signaling Peptides and Proteins*/metabolism, Humans ; Animals ; Mice ; Ligands ; Calcium-Binding Proteins/metabolism ; Signal Transduction/physiology ; Receptors, Notch/metabolism |
| مستخلص: | The Notch pathway regulates cell fate decisions and is an emerging target for regenerative and cancer therapies. Recombinant Notch ligands are attractive candidates for modulating Notch signaling; however, their intrinsically low receptor-binding affinity restricts their utility in biomedical applications. To overcome this limitation, we evolved variants of the ligand Delta-like 4 with enhanced affinity and cross-reactivity. A consensus variant with maximized binding affinity, Delta MAX , binds human and murine Notch receptors with 500- to 1,000-fold increased affinity compared with wild-type human Delta-like 4. Delta MAX also potently activates Notch in plate-bound, bead-bound and cellular formats. When administered as a soluble decoy, Delta MAX inhibits Notch in reporter and neuronal differentiation assays, highlighting its dual utility as an agonist or antagonist. Finally, we demonstrate that Delta MAX stimulates increased proliferation and expression of effector mediators in T cells. Taken together, our data define Delta MAX as a versatile tool for broad-spectrum activation or inhibition of Notch signaling. (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.) |
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| معلومات مُعتمدة: | R01 CA233512 United States CA NCI NIH HHS; R35 GM133482 United States GM NIGMS NIH HHS; DP5 OD024558 United States OD NIH HHS; P01 CA250984 United States CA NCI NIH HHS; P30 CA076292 United States CA NCI NIH HHS; R01 CA184185 United States CA NCI NIH HHS; R01 CA273034 United States CA NCI NIH HHS; R35 CA220340 United States CA NCI NIH HHS; R01 CA262121 United States CA NCI NIH HHS |
| المشرفين على المادة: | 0 (Ligands) 0 (Adaptor Proteins, Signal Transducing) 0 (Intercellular Signaling Peptides and Proteins) 0 (Calcium-Binding Proteins) 0 (Receptors, Notch) 0 (DLL4 protein, human) 0 (DLL4 protein, mouse) |
| تواريخ الأحداث: | Date Created: 20220901 Date Completed: 20221230 Latest Revision: 20240422 |
| رمز التحديث: | 20240423 |
| مُعرف محوري في PubMed: | PMC10132381 |
| DOI: | 10.1038/s41589-022-01113-4 |
| PMID: | 36050494 |
| قاعدة البيانات: | MEDLINE |
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Full Text Finder | تدمد: | 1552-4469 |
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| DOI: | 10.1038/s41589-022-01113-4 |