PTP-MEG2: Regulation, Substrates, Biology

PTP-MEG2：调节、底物、生物学

• 批准号: 6662338
• 负责人: Tomas M Mustelin
• 金额: $ 11.14万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6662338
• 关键词: biological signal transduction; cell differentiation; cell growth regulation; enzyme activity; enzyme substrate; genetically modified animals; green fluorescent proteins; laboratory mouse; mass spectrometry; phospholipids; phosphorylation; protein binding; protein structure function; protein transport; protein tyrosine phosphatase; secretory protein; southern blotting

DESCRIPTION (provided by applicant): Phosphorylation of proteins on tyrosyl residues is a key mechanism for the control of cell growth, differentiation and development. Phosphate is selectively removed from tyrosyl residues by a family of enzymes known as protein tyrosine phosphatases (PTPases), which play important roles in preventing malignant transformation, limiting signal transduction and in the maintenance of normal cell physiology. This proposal focuses on one particular PTPase, the 68-kDa PTP-MEG2, which contains a novel type of phospholipid-binding domain, a CRASH domain. We have found that this domain binds phosphatidylinositol-3,4,5-trisphosphate (Ptdlns(3,4,5)P3) with high affinity and that PTP-MEG2 is located on secretory vesicles in mast cells, T cells, and other cell types. We hypothesize that the physiological function of PTP-MEG2 is to regulate the formation or homeostasis of dense-core secretory vesicles of the regulated secretory pathway in hematopoietic and other cells. We will focus on this topic by addressing the following 3 specific aims: 1) Regulation of PTP-MEG2 by inositol phospholipids. 2) Identification of substrates for PTP-MEG2. 3) Physiological function of PTP-MEG2. Our overall goal is to understand the physiological function of PTPases in tyrosine phosphorylation-mediated cellular processes. PTP-MEG2 is a unique member of this class of enzymes and appears to integrate phosphoinositide signaling into tyrosine dephosphorylation and the regulation of intracellular vesicle traffic. This represents a novel and unexpected crosstalk between these three important aspects of cell biology. Thus, the significance of our work is high and it may bring many new insights that could be exploited for the treatment of human disease.

描述（由申请人提供）：酪氨酰残基上蛋白质的磷酸化是控制细胞生长、分化和发育的关键机制。蛋白质酪氨酸磷酸酶 (PTPase) 家族可以选择性地去除酪氨酰残基上的磷酸盐，这些酶在防止恶性转化、限制信号转导和维持正常细胞生理学方面发挥着重要作用。该提案重点关注一种特殊的 PTPase，即 68 kDa PTP-MEG2，它包含一种新型的磷脂结合域，即 CRASH 域。我们发现该结构域以高亲和力结合磷脂酰肌醇-3,4,5-三磷酸 (Ptdlns(3,4,5)P3)，并且 PTP-MEG2 位于肥大细胞、T 细胞和其他细胞类型的分泌囊泡上。我们假设 PTP-MEG2 的生理功能是调节造血细胞和其他细胞中受调节分泌途径的致密核心分泌囊泡的形成或稳态。我们将通过解决以下 3 个具体目标来重点关注该主题：1）肌醇磷脂对 PTP-MEG2 的调节。 2) PTP-MEG2底物的鉴定。 3）PTP-MEG2的生理功能。我们的总体目标是了解 PTPase 在酪氨酸磷酸化介导的细胞过程中的生理功能。 PTP-MEG2 是此类酶的独特成员，似乎将磷酸肌醇信号转导整合到酪氨酸去磷酸化和细胞内囊泡运输的调节中。这代表了细胞生物学这三个重要方面之间的新颖且意想不到的串扰。因此，我们的工作意义重大，它可能带来许多新的见解，可用于治疗人类疾病。