Oxidation-dependent degradation as a novel principle for regulation of protein-tyrosine phosphatases - role of PTP DEP-1 oxidation for transformation in AML

细胞表面受体是细胞-细胞和细胞-基质通讯以及通过可溶性因子进行信息交换的重要元素。几种受体通过激酶功能引发信号转导，该信号转导功能要么是受体分子本身的一部分，要么被招募到受体。信号的启动涉及受体至少两个相关亚单位分子的相互酪氨酸磷酸化。与其胞外配体的相互作用被认为触发了这种联系(通常称为二聚化)。通过使用有毒试剂，我们发现这些酪氨酸激酶的去磷酸化是调节过程中的一个决定性过程。有毒物质通过氧化(或与其活性中心的半胱氨酸反应)使受体酪氨酸磷酸酶失活。结果，磷酸化和去磷酸化之间的平衡向自发的(配体无关的)激酶活性增加转变。这些数据表明，受体依赖的信号的很大一部分是由密切相关的酪氨酸磷酸酶的活性调节的。我们推测，生理调节--就像有毒物质的调节一样--利用了氧化还原反应。该项目试图拓宽磷酸酶调控重要性的证据，通过下面描述的技巧识别受体底物磷酸酶对，并探索蛋白质酪氨酸磷酸酶的氧化还原是如何被催化的。

Cell surface receptors are important elements in cell-cell and cell-matrix communications as well as in the exchange of information through soluble factors. Several receptors elicit a signal transduction cascade through kinase function which is either part of the receptor molecule itself or gets recruited to the receptor. Initiation of signalling involves mutual tyrosine phosphorylation of at least two associated subunit molecules of the receptor. The interaction with its extracellularligand is thought to trigger this association (usually called dimerization). By the use of toxic agents we have discovered that dephosphorylation of these tyrosine kinases is a decisive process in the regulation. The toxic agents inactivate receptor tyrosine phosphatases by oxidizing (or reacting with) a cysteine in their active centers. As a result the balance between phosphorylation and dephosphorylation is shifted towards increased spontaneous (ligand-independent) kinase activity. These data suggest that a major part of the receptor dependent signalling is regulated by the activity of a closely associated tyrosine phosphatase. We speculate that the physiological regulation - like that by toxic agents - makes use of oxidation-reduction reactions. This project attempts to broaden the evidence for the significance of phosphatase regulation, to identify - by a trick to be described below - receptor substrate phosphatase pairs, and to explore how oxidation-reduction of protein tyrosine phosphatase is catalyzed.