PTP-MEG2: Regulation, Substrates, Biology

描述(由申请人提供)：酪氨酸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。蛋白酪氨酸磷酸酶(PTPase)是一类被称为蛋白酪氨酸磷酸酶(PTPase)的酶，选择性地从酪氨酸残基中去除磷酸盐，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方面发挥着重要作用。该提案针对的是一种特殊的PTPase，即68 kDa的PTP-MEG2，它含有一种新型的磷脂结合结构域，即CRASH结构域。我们发现该结构域与磷脂酰肌醇-3，4，5-三磷酸(Ptdlns(3，4，5)P3)高亲和力结合，PTP-MEG2定位于肥大细胞、T细胞和其他细胞类型的分泌小泡上。我们推测，PTP-MEG2的生理功能是调节造血细胞和其他细胞分泌途径中致密核分泌囊泡的形成或稳态。我们将通过解决以下三个具体目标来关注这一主题：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是这类酶中唯一的成员，它似乎将肌醇磷脂信号整合到酪氨酸去磷酸化和细胞内小泡交通的调节中。这代表了细胞生物学的这三个重要方面之间的一种新奇和意想不到的串扰。因此，我们的工作具有很高的意义，它可能会带来许多新的见解，可以用来治疗人类疾病。

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.