CHIMAERINS--RECEPTORS FOR DIACYLGLY AND PHORBOL ESTERS

描述：尽管众所周知，受体介导的 二酰甘油(DAG)水平升高导致蛋白质激活 激酶C(PKC)，这种亲脂性第二信使的新受体，并 它的类似物佛波酯肿瘤促进剂是最近发现的： 奇马林。与PKC不同的是，N-嵌合体不具有激酶 域。其催化结构域与BCR(断点簇)有很高的同源性 区域)，一种与费城染色体易位有关的蛋白质 慢性粒细胞白血病。与BCR一样，n-嵌合体也具有GTP酶激活功能 P21Rac是一种小的GTP结合蛋白，它的蛋白质(GAP)活性 在细胞骨架结构、基因转录、细胞 生长和恶变。嵌合体家族的扩大 克隆新的异构体(a1-或“n-”、a2-、b1-和b2-嵌合体) 表示下游可能存在高度的复杂性 DAG触发的通路。A2和b2嵌合体具有 其结构上的Sh2基序预测这些嵌合体亚型可能 与酪氨酸磷酸化蛋白有关，这可能调节它们的 活动性或本地化，因此暗示不同的 信号通路。这项提案的总体目标是评估 第二信使DAG和佛波酯是否为肿瘤促进剂 除了调节PKC的嵌合体活性外，还调节嵌合体的活性，并确定 这一途径在细胞中被激活的生物学后果。 在具体目标2中，他将识别与嵌合体相关的蛋白质。 含磷酸酪氨酸蛋白的α2和2嵌合体的SH2结构域。我们会 还要研究佛波酯诱导的易位是否会导致 嵌合体与特定靶标或锚定蛋白的结合。在……里面 具体目标3他将重点介绍嵌合体的生物学作用。我们的 假设嵌合体可能影响p21Rac介导的反应， 从而影响细胞生长、恶变和细胞 在形态上。Kazanietz的研究有可能定义新的“PKC 佛波酯肿瘤促进剂和DAG的独立途径，以及 希望能对控制恶性肿瘤的事件有新的见解 转型。佛波醇酯类化合物的目标表征 对阐明它们的生物学行为和解开它们的 参与致癌机制的途径。

DESCRIPTION: Although it is well established that receptor-mediated elevation in diacylglycerol (DAG) levels leads to activation of protein kinase C (PKC), a novel receptor for this lipophilic second messenger and its analogs, the phorbol ester tumor promoters, was recently discovered: chimaerin. In contrast to PKC, N-chimaerin does not possess a kinase domain. Its catalytic domain has high homology to BCR (breakpoint cluster region), a protein involved in Philadelphia chromosome translocation in chronic myelogenous leukemia. Like BCR, n-chimaerin has GTPase-activating protein (GAP) activity for the p21Rac, a small GTP-binding protein which plays a central role in cytoskeletal structure, gene transcription, cell growth and malignant transformation. The expansion of the chimaerin family with the cloning of new isoforms (a1- or "n-",a2-,b1-,andb2-chimaerins) indicates that a high degree of complexity may exist in the downstream pathways triggered by DAG. The fact that the a2- and b2-chimaerins possess SH2 motifs on their structure predicts that these chimaerin isoforms may associate with tyrosine phosphorylated proteins which may regulate their activity or localization, therefore suggesting crosstalk between different signaling pathways. The overall goal of this proposal is to evaluate whether the second messenger DAG and the phorbol ester tumor promoters regulate the chimaerin activity in addition to that of PKC, and to determine the biological consequences of the activation of this pathway in the cell. In Specific Aim 2, he will identify proteins that associate to chimaerins. The SH2 domains of a2- and 2-chimaeri withphosphotyrosine proteins. We will also study whether translocation induced by phorbol esters leads to the association of chimaerins with specific targets or anchoring proteins. In Specific Aim 3 he will focus on the biological roles of chimaerins. Our hypothesis is that chimaerins may affect those responses mediated by p21Rac, and therefore affect cell growth, malignant transformation, and cell morphology.Dr. Kazanietz's research has the potential for defining new "PKC independent" pathways for the phorbol ester tumor promoters and DAG, and hopefully will yield new insights into the events controlling malignant transformation. The characterization of the targets for the phorbol esters would be valuable to clarify their biological actions and also to unravel pathways involved in the mechanisms of carcinogenesis.