PHOSPHOLIPIDN METABOLISM ACTIVATED BY V-SRC

本提案的目的是了解磷脂 代谢，由致癌蛋白酪氨酸激酶（PTK）激活v- Src参与启动复杂的细胞内信号 通过v-Src最终导致转型。 的机制 v-Src和其他PTK产生复杂的细胞内信号， 经常导致细胞增殖的原因还不清楚。 到 产生诱导细胞增殖过程所必需的信号 并没有得到很好的理解。 为了产生必要的信号， 像细胞增殖一样复杂的过程，许多细胞内信号传导 分子可能被PTK招募。 近年来，它已成为 越来越明显的是， 膜远远超过作为生物屏障所需的功能。 磷脂，其构成膜脂质的大部分，可以是 通过许多不同的代谢途径代谢成各种生物活性分子， 酶活性 在该提案中，实验描述为， 将继续我们的观察，即v-Src诱导的 甘油二酯的结果不是从更确定的机制， 磷脂酶C介导的磷酸肌醇水解，而是由 磷脂酶D介导的磷脂酰胆碱水解（Song et 例如，1991年）。 在该提案中，描述的实验将1） 表征了v-Src活性磷脂的机制 代谢和2）表征磷脂代谢物，包括 甘油二酯、甘油单酯、磷脂酸和可能的溶血- 响应于v-Src产生的磷脂酸。 恶性转化是指细胞的逐渐失去控制， 细胞内信号传导机制。 许多酶参与了 膜脂代谢产生的复杂信号提供了许多 干扰细胞内信号的潜在靶点， 导致恶性转化。 本文提出的研究将 识别干扰PTK启动的 有助于转化的细胞内信号。

The objective of this proposal is to understand how phospholipid metabolism, activated by the oncogenic protein-tyrosine kinase (PTK) v- Src, contributes to the complex set of intracellular signals initiated by v-Src that ultimately lead to transformation. The mechanisms by which v-Src and other PTKs generate the complex intracellular signals that frequently lead to cell proliferation is not well understood. To generate the signals necessary to induce a process as cell proliferation is not well understood. To generate the signals necessary to induce a process as complex as cell proliferation, many intracellular signalling molecules ar likely recruited by PTKs. In recent years it has become increasingly apparent that the complexity of the lipid components in membranes far exceeds that required for function as a biological barrier. Phospholipids, which comprise the majority of membrane lipids, can be metabolized to variety of biologically active molecules by many distinct enzymatic activities. In this proposal experiments are described that will follow up on our observation that v-Src-induced increases in diglycerides results not from the more established mechanism of phospholipase C-mediated hydrolysis of phosphoinositides, but rather by a phospholipase D-mediated hydrolysis of phosphatidylcholine (Song et al., 1991). In this proposal, experiments are described that will 1) characterize the mechanism by which v-Src activities phospholipid metabolism and 2) characterize the phospholipid metabolites including diglycerides, monoglycerides, phosphatidic acid and possibly lyso- phosphatidic acid generated in response to v-Src. Malignant transformation involves a progressive loss of control of intracellular signalling mechanisms. The many enzymes involved in the complex signals generated by metabolism of membrane lipids provides many potential targets for interfering with the intracellular signals that may contribute to malignant transformation. The studies proposed here will identify potential targets for interfering with the PTK-initiated intracellular signals that contribute to transformation.