Regulatory Pathways of SR Protein Kinases

SR蛋白激酶的调控途径

• 批准号: 9235874
• 负责人: JOSEPH ADAMS
• 金额: $ 31.78万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9235874
• 关键词: Address; Affect; Affinity; Alzheimer' s Disease; Arginine; Ataxia; Attention; Biological Assay; C-terminal; Cardiovascular Diseases; Carrier Proteins; Catalysis; Cell Nucleus; Cell physiology; Cells; Complex; Cytoplasm; Disease; EGF gene; Enzymatic Biochemistry; Enzymes; Excision; Family; Funding; Genes; Growth Factor; Human; Kinetics; Knowledge; Lead; Link; Macromolecular Complexes; Malignant Neoplasms; Messenger RNA; Molecular Chaperones; Muscular Dystrophies; Nature; Normal Cell; Nuclear; Nuclear Import; Nuclear Protein; Organism; Parkinsonian Disorders; Peptide Hydrolases; Phosphorylation; Phosphotransferases; Protein Family; Protein Kinase; Protein Splicing; Proteins; Proteome; RNA; RNA Splicing; Reaction; Regulation; Regulatory Pathway; Research Project Grants; Role; Serine; Site; Spliced Genes; Spliceosomes; Techniques; U1 Small Nuclear Ribonucleoprotein; catalyst; cellular imaging; genome-wide; human disease; inorganic phosphate; mRNA Precursor; mutant; novel; nucleocytoplasmic transport; pressure; protein transport; public health relevance; release factor

Project Summary/Abstract: Splicing converts a single gene into multiple unique mRNA fragments to expand the size of the proteome and regulate cell function. While splicing is integral for normal function in complex organisms, mistakes in splice-selection can lead to disease. In fact, splicing errors are associated with numerous human disorders including muscular dystrophy, Alzheimer's disease, parkinsonism, cardiovascular disease, ataxias and cancers. Splicing occurs at the spliceosome, a macromolecular complex that includes both RNA and protein. In the latter group, SR proteins are essential splicing factors that control where the spliceosome assembles on precursor mRNA. SR proteins contain C-terminal domains rich in arginine-serine repeats whose polyphosphorylation controls splice-site selection. The SRPK family of protein kinases phosphorylates these RS domains directing SR proteins into the nucleus for splicing activity. While SRPKs are normally localized to the cytoplasm for this function, they can enter the nucleus under certain conditions but their function in this cellular compartment is not well understood. We will now investigate the functions of SRPKs in both the cytoplasm and nucleus using genome-wide splicing assays, cell imaging, fast-mixing kinetics, protease footprinting and structural techniques. We will determine how the unique SRPK phosphorylation mechanism governs transport of SR proteins from the cytoplasm to the nucleus. We will explore factors that regulate SRPK nuclear import through a novel kinase- kinase complex. Finally, we will investigate how this complex affects splicing reactions through the mobilization of SR proteins in the nucleus. Overall, the studies outlined in this proposal will greatly expand our knowledge of SRPK-induced phosphorylation of SR proteins and their splicing function.

项目总结/文摘: