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Understanding how ciliary gene mutations affect the processing and activity of Gli2 and Gli3 transcription factors

了解纤毛基因突变如何影响 Gli2 和 Gli3 转录因子的加工和活性

基本信息

批准号：
10439864
负责人：
BAOLIN WANG
金额：
$ 36.66万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10439864
关键词：
Activator Appliances Affect Antibodies Binding Proteins C-terminal Cell Proliferation Cell surface Cells Centrioles Centrosome Cilia Complex Congenital Abnormality Cyclic AMP-Dependent Protein Kinases Data Defect Development Embryonic Development Erinaceidae Exhibits F-Box Proteins Family G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs Gene Mutation Genes Genetic Transcription Glycogen Synthase Kinase 3 Goals Human Kidney Length Malignant Neoplasms Mediating Microtubules Molecular Mothers Mus Mutate Mutation Organ Organelles Pathway interactions Phenotype Phosphorylation Play Process Proteins Retina Role Sensory Serine Signal Transduction Signaling Molecule Signaling Protein Site Structure Threonine Transcription Coactivator Ubiquitination Vertebrates Vesicle Zinc Fingers base casein kinase I cell fate specification ciliopathy drug development embryo cell extracellular hedgehog signal transduction human disease insight multicatalytic endopeptidase complex mutant receptor smoothened signaling pathway therapeutic target transcription factor ubiquitin-protein ligase

项目摘要

Abstract The primary cilium is a solitary microtubule-based organelle that protrudes from the cell surface and is found on most vertebrate cells. It serves as a sensory organelle in organs such as the kidney and retina and also functions in transducing extracellular signals such as Hedgehog (Hh), a secreted signaling molecule that is essential for embryo development and cell proliferation and differentiation. Defects in cilia structure and function are associated with a diverse array of developmental abnormalities, collectively termed “ciliopathies”. Hh signaling in vertebrates occurs in primary cilia and is primarily mediated by Gli2 and Gli3 zinc finger- containing transcription factors. Gli2 is primarily an activator, whereas Gli3 is mostly a repressor, though it also exhibits a weak activator function. Consistent with their functions, most full-length Gli3 (Gli3FL) is proteolytically processed to generate a C-terminally truncated repressor in the absence of Hh signaling, while only a small fraction of Gli2FL is processed. Gli2/Gli3 processing is induced by phosphorylation of the first four of the six serine/threonine residues at their C-termini by protein kinase A (PKA) and then by glycogen synthase kinase 3 (GSK3) and casein kinase 1 (CK1). The multi-phosphorylated Gli2/Gli3 are then ubiquitinated and partially degraded by the proteasome. Hh signaling inhibits Gli2/Gli3 processing by suppressing PKA-mediated phosphorylation of the first four PKA sites and also activates Gli2FL/Gli3FL by inhibiting the phosphorylation of the fifth and sixth PKA sites in their C-termini. Defects in cilia structure and function mostly affect Hh signaling. One near universal hallmark of ciliary gene mutants at the molecular level is the reduced Gli2/Gli3 processing. Interestingly, however, the levels of Gli2/Gli3 activity in ciliary gene mutants vary from none to elevated depending on mutated ciliary genes. This suggests that the mechanism by which ciliary proteins regulate Hh signaling is diverse and complex. While the effect of ciliary mutations on Hh signaling is well established, the molecular mechanisms underlying these effects are thus far unknown. The goal of this proposal is to elucidate the molecular mechanisms by which Gli2/Gli3 processing, stability, and activity are altered in ciliary gene mutants.

摘要