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Regulation of Mutationally Activated Gq/11

突变激活 Gq/11 的调控

基本信息

批准号：
10376872
负责人：
PHILIP B WEDEGAERTNER
金额：
$ 31.2万
依托单位：
THOMAS JEFFERSON UNIVERSITY
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：
2021-04-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10376872
关键词：
Address Adult Binding Biochemical Biological Assay Biosensor Blindness Blood capillaries Cardiovascular Physiology Cell Differentiation process Cell membrane Cell model Cell physiology Cells Codon Nucleotides Congenital Hemangioma Cultured Cells Cyclodepsipeptides Data Disease Endocrine System Diseases Fluorescence Microscopy G-Protein-Coupled Receptors GNAQ gene GTP Binding GTP-Binding Proteins Genes Glutamine Guanine Nucleotide Exchange Factors Guanosine Triphosphate Heart Diseases Heterotrimeric G Protein Subunit Heterotrimeric GTP-Binding Proteins Hydrolysis Hypertension Immune Immunofluorescence Microscopy Knowledge Link Location Malignant Neoplasms Mediating Membrane Mitogen-Activated Protein Kinases Modeling Molecular Mutation Mutation Analysis Natural Products Neoplasm Metastasis Neoplasms in Vascular Tissue Neurotransmitters Oncogenic Pathway interactions Patients Pharmacology Phospholipase C Physiological Physiological Processes Plasma Cells Play Protein Subunits Proteins Refractory Regulation Research Project Grants Research Proposals Resistance Role Signal Pathway Signal Transduction Smell Perception Somatic Mutation Sturge-Weber Syndrome Surface Taste Perception Testing Uveal Melanoma Vision Work base cell growth regulation cell motility disease-causing mutation experience extracellular genetic regulatory protein human disease inhibitor live cell microscopy malformation malignant neoplasm of eye mutant nervous system disorder neuron development new therapeutic target novel palmitoylation protein function receptor-mediated signaling reconstitution resistance mechanism response rho therapeutic target trafficking

项目摘要

Abstract Heterotrimeric G proteins () are well known for their function in linking G protein-coupled receptors (GPCRs) to a variety of intracellular responses, and thereby playing essential roles in transmitting a wide variety of extracellular signals into regulation of countless physiological processes. However, it has also become increasingly recognized that G proteins can function independently of GPCRs. Highlighting the physiological relevance of GPCR-independent G protein function, constitutively activating somatic mutations in several G subunits have been identified and shown to contribute to human disease, most prominently in cancer. This research project focuses on constitutively active mutants of the highly similar q and 11 subunits, collectively termed q/11. Mutations at one of two hotspot residues, that result in inhibition of the GTP hydrolysis turn-off mechanism, can convert q/11 into an oncogenic driver of uveal melanoma, and such constitutively activating q/11 mutations have also been associated with vascular tumors, capillary malformation, congenital hemangioma and Sturge Weber syndrome. This research project will focus on uncovering basic cellular mechanisms regulating signaling by mutationally activated q/11. G subunits are typically thought as exceptionally difficult proteins for which to develop pharmacological or molecular inhibitors. However, numerous recent studies have demonstrated that the highly similar natural products YM-254890 and FR900359 are effective inhibitors of wild type and mutationally activated q/11. Our work has uncovered an unexpected mechanism of action of these inhibitors leading to the hypothesis that YM- 254890 and FR900359 inhibit q/11, at least in part, by regulating subcellular localization of q/11. Understanding the novel mechanisms of inhibition and cellular regulation of mutationally activated q/11 may suggest novel therapeutic targets or approaches for disrupting dysregulated signaling. The objectives in this research project will be pursued by a variety of experimental approaches, including using cultured cells, immunofluorescence microscopy, fluorescence microscopy of live cells, constitutive targeting to specific subcellular locations, biosensors, pharmacological inhibitors, mutational analysis, and biochemical assays.

摘要