MOLECULAR GENETIC OF TYROSINE KINASE AND RAS FUNCTION

受体酪氨酸激酶(RTK)是一种跨膜蛋白， 将荷尔蒙信号从细胞外部传递到细胞内部。 RTK的激活可以控制细胞代谢的许多方面， 生长和分化。RTK信令不充分或不适当 可导致糖尿病等疾病(胰岛素受体不足 信号)，某些形式的癌症(如家族性甲状腺髓样癌 由RET RTK过度活跃的信号引起的癌症)，以及 发育异常(如先天性巨结肠症由 RET RTK发送的信号不充分)。拟议研究的目的 是研究RTKs是如何通过生物化学控制细胞功能的。 我们正在通过研究特定RTK的行动来解决这个问题， 果蝇七星基因的产物。我们已经选择了 研究SEVENLESS，因为它有能力进行遗传和 难以或不可能进行的生化研究 在脊椎动物中。 Seven less RTK的激活充当了一个开关，它会导致 果蝇眼睛每个亚单位内的单个细胞发育为 感光细胞。我们的方法是识别 通过表征减弱的突变来确定七个信号通路 七个小时的信号。我们已经证明了三种蛋白质的活性 (开瓶器，塞文斯和残疾人的女儿)是必不可少的 七喜能有效地诱导感光细胞发育。我们的结果 已经表明，被禁用的是一种可能的底物的激酶活性 七人组的。开瓶器编码一种蛋白质酪氨酸磷酸酶 我们已经证明了通过去磷酸化七个无主的女儿 蛋白。拟议研究的目标是进一步确定 七种信号途径：1)生化和遗传 《七夕之女》的规律性与角色研究 在七次信号转导过程中，2)进一步的分子特征 其产品与开瓶器及其子代协作的基因 七次信号传递中的七次，以及3)生化研究 被禁用的功能。由于RTK下游的生化途径 在苍蝇和人类之间高度保守，我们希望有一个更充分的 了解SEVENLESS信令将为 了解人类RTK信号的重要方面。

Receptor Tyrosine Kinases (RTKs) are transmembrane proteins that transduce hormonal signals from the exterior to the interior of cells. The activation of RTKs can control many aspects of cellular metabolism, growth, and differentiation. Inadequate or inappropriate RTK signaling can result in diseases such as diabetes (inadequate insulin receptor signaling), certain forms of cancer (such as familial medullary thyroid carcinoma caused by overly active signaling by the RET RTK), and developmental abnormalities (such as Hirschsprung's disease caused by inadequate signaling by the RET RTK). The aim of the proposed research is to investigate how RTKs biochemically control cellular functions. We are addressing this issue by studying the action of a particular RTK, the product of the sevenless gene of Drosophila. We have chosen to study sevenless because of the ability to perform genetic and biochemical studies that are either difficult or impossible to conduct in vertebrate organisms. The activation of the sevenless RTK serves as a switch that causes a single cell within each subunit of the Drosophila eye to develop as a photoreceptor cell. Our approach is to identify components of the sevenless signaling pathway by characterizing mutations which attenuate sevenless signaling. We have shown that the activity of three proteins (corkscrew, daughter of sevenless and disabled) are essential for sevenless to efficiently induce photoreceptor development. Our results have shown that disabled is a probable substrate for the kinase activity of sevenless. Corkscrew encodes a protein tyrosine phosphatase which we have shown to function by dephosphorylating the daughter of sevenless protein. The goals of the proposed research are to further characterize the sevenless signaling pathway by: 1) biochemical and genetic investigations of the regulation and role of daughter of sevenless during sevenless signaling, 2) molecular characterization of further genes whose products collaborate with corkscrew and daughter of sevenless during sevenless signaling, and 3) biochemical investigation of disabled function. Since the biochemical pathways downstream of RTKs are highly conserved between flies and humans, we hope that a fuller understanding of sevenless signaling will provide the basis for understanding important aspects of human RTK signaling.