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A mechanism for tyrosine phosphorylation of extracellular matrix proteins

细胞外基质蛋白酪氨酸磷酸化的机制

基本信息

批准号：
9525550
负责人：
BJORN REINO OLSEN
金额：
$ 22.37万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9525550
关键词：
Affect Alternative Splicing Binding Bioinformatics Cell Line Cell Surface Proteins Cell surface Cells Collagen Cultured Cells Data Databases Development Dimensions Disease Drug or chemical Tissue Distribution Environment Enzymes Epithelial Cells Exons Extracellular Matrix Extracellular Matrix Proteins Extracellular Protein Extracellular Space FGFR1 gene FGFR2 gene FGFR3 gene FarGo Fibroblast Growth Factor Fibroblast Growth Factor Receptors Future Generations Genes Hand Heparitin Sulfate Homeostasis Human In Vitro Lead Ligand Binding Domain Ligands Lung Matrix Metalloproteinases Molecular Morphogenesis Mus Names Organ Culture Techniques Pathway interactions Pattern Phosphoric Monoester Hydrolases Phosphorylation Phosphorylation Site Phosphotransferases Property Protein Dephosphorylation Protein Isoforms Protein Kinase Protein Tyrosine Kinase Proteins Publishing RNA Splicing Receptor Protein-Tyrosine Kinases Receptor Signaling Research Personnel Role Site Skin Specificity Squamous cell carcinoma Structure of parenchyma of lung System Tamoxifen Techniques Teratoma Tissues Transcript Transgenes Transitional Cell Carcinoma Transmembrane Domain Tyrosine Tyrosine Phosphorylation Urothelium Variant Wound Healing base craniofacial cranium design dimer disulfide bond experimental study extracellular in vivo insight knock-down loss of function novel overexpression protein function receptor tool

项目摘要

Summary A great number of proteins in the extracellular matrix are phosphorylated; yet practically all known kinases operate inside cells and are unable to catalyze phosphorylation of secreted proteins. The recent discovery of two secreted kinases, Fam20C and VLK, represents a major step forward in understanding how proteins outside cells can be phosphorylated at multiple sites. However, numerous extracellular proteins are phosphorylated at sites that are clearly not targets of these two kinases. Thus, additional secreted kinases must exist, raising questions about how to best identify them and determine what their functions may be. In this application the investigators describe how a bioinformatics strategy led to the discovery of secreted variants of transmembrane-spanning, ligand-activated, fibroblast growth factor receptor tyrosine kinases (FGFRs); with the variants consisting of the fibroblast growth factor-binding domain directly connected to the kinase domain. Based on preliminary data, showing that the secreted Fgfr2 kinase variant is expressed in multiple tissues in mice, the investigators have made several constructs for expression of the kinase in cultured cells and they have generated mice that can be induced to express the kinase in different cells and tissues. In Aim 1, in vitro and in vivo studies are directed at determining the specificity of the secreted FGFR2 kinase in phosphorylation of extracellular matrix proteins in skin, lung and craniofacial (skull) tissues. In Aim 2 experiments are designed to provide insights into the roles of the secreted FGFR2 kinase in developing lungs of mice and in three- dimensional organ cultures of lung tissues, allowing studies of cellular and molecular mechanisms that may be regulated by the secreted FGFR2 kinase. If successful, these studies are likely to break new ground and lead to future studies opening an entirely new chapter in the understanding of how cells interact with and regulate the properties of extracellular matrix molecules.

总结