PHOSPHOLIPIDN METABOLISM ACTIVATED BY V-SRC

这项建议的目的是了解磷脂是如何 代谢，由致癌蛋白-酪氨酸激酶(PTK)v-激活- SRC参与启动的复杂的细胞内信号集合 通过v-Src最终导致转变。它们的作用机制 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机制还不是很清楚。至 产生诱导细胞增殖过程所需的信号 还没有被很好地理解。以产生必要的信号来诱导 像细胞增殖一样复杂的过程，许多细胞内信号 分子很可能是被PTK招募的。近年来，它已经成为 越来越明显的是，体内脂质成分的复杂性 膜远远超过作为生物屏障发挥作用所需的能力。 构成大多数膜脂的磷脂可以是 通过许多不同的方式代谢成各种生物活性分子 酶活性。在这项建议中，描述了实验 将跟进我们的观察结果，即V-Src诱导的 二甘油三酯的产生不是由于更成熟的 磷脂酶C介导的磷脂酰肌醇的水解，而不是通过 磷脂酶D介导的磷脂酰胆碱(Song Et)的水解 Al.，1991)。在这份提案中，描述的实验将1) 表征v-Src激活磷脂的机制 代谢和2)表征磷脂代谢物，包括 甘油二酯，单甘酯，磷脂酸，可能还有溶质- V-Src反应生成的磷脂酸。 恶性转化包括逐渐失去对 细胞内信号传递机制。涉及到的许多酶 由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可能 会导致恶变。这里提出的研究将 确定干扰PTK启动的潜在目标 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.