Role of a Novel Secreted Protein Tyrosine Kinase in Development

新型分泌蛋白酪氨酸激酶在发育中的作用

• 批准号: 8679884
• 负责人: MALCOLM R. WHITMAN
• 金额: $ 29.66万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-09 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8679884
• 关键词: Area; Atherosclerosis; Biological Models; Cartilage; Cells; Data; Data Set; Development; Disease; Embryo; Embryonic Development; Environment; Event; Extracellular Matrix; Extracellular Matrix Proteins; Fibrosis; Lead; Location; Matrix Metalloproteinases; Morphogenesis; Neoplasm Metastasis; Pathogenesis; Pathology; Pathway interactions; Pattern; Peptide Signal Sequences; Phosphoproteins; Phosphorylation; Phosphotransferases; Protein Tyrosine Kinase; Proteins; Publishing; Rana; Regulation; Reporting; Role; Structure; Tissues; Tyrosine; Tyrosine Phosphorylation; Work; Xenopus; base; craniofacial; extracellular; in vivo; interest; novel; public health relevance; research study; tool; tumor

DESCRIPTION (provided by applicant): The microenvironment in which cells reside in tissues, the extracellular matrix (ECM), is increasingly recognized as a major regulator of embryonic morphogenesis. We propose to use the Xenopus embryo as a model system to study a novel mechanism of regulation of ECM, the tyrosine phosphorylation of secreted proteins. In our preliminary experiments, we have identified a protein tyrosine kinase that, unlike any previously known tyrosine kinase, is synthesized directly into the secretory pathway, and which phosphorylates extracellular matrix proteins. Our preliminary data indicate that this novel kinase as a key role in early craniofacial patterning. The activity and location of this kinase provides the first explanation for a large body of published phosphoproteomic work reporting conserved tyrosine phosphorylations in ECM proteins secreted via the canonical signal peptide pathway. We plan to use frog embryos to study the function of this secreted tyrosine kinase in early craniofacial morphogenesis, and identify and characterize tyrosine phosphorylated substrates in an in vivo context. These studies will provide the basis for an entirely new area of study, the reversible regulation of secreted proteins by tyrosine phosphorylation during embryogenesis. Dynamic regulation and remodeling of ECM is also central to a wide range of disease pathologies (e.g. tumor metastasis, fibrosis, atherosclerosis), and therefore the regulation of ECM proteins by tyrosine phosphorylation is likely to also have important implications for the modulation of disease pathogenesis.

描述（由申请人提供）：细胞驻留在组织中的微环境，即细胞外基质（ECM），越来越多地被认为是胚胎形态发生的主要调节因子。我们建议使用非洲爪蟾胚胎作为一个模型系统来研究一种新的机制，ECM的分泌蛋白的酪氨酸磷酸化的调节。在我们的初步实验中，我们已经确定了一种蛋白酪氨酸激酶， 任何先前已知的酪氨酸激酶直接合成到分泌途径中，并使细胞外基质蛋白磷酸化。我们的初步数据表明，这种新的激酶作为一个关键作用，在早期颅面图案。该激酶的活性和位置为大量已发表的磷酸蛋白质组学工作提供了第一个解释，这些工作报告了通过经典信号肽途径分泌的ECM蛋白中保守的酪氨酸磷酸化。我们计划使用青蛙胚胎来研究这种分泌的酪氨酸激酶在早期颅面形态发生中的功能，并在体内环境中识别和表征酪氨酸磷酸化底物。这些研究将为一个全新的研究领域提供基础，即胚胎发生过程中酪氨酸磷酸化对分泌蛋白的可逆调节。ECM的动态调节和重塑也是广泛的疾病病理学（例如肿瘤转移、纤维化、动脉粥样硬化）的核心，因此通过酪氨酸磷酸化调节ECM蛋白可能也对疾病发病机制的调节具有重要意义。