MOLECULAR GENETIC OF TYROSINE KINASE AND RAS FUNCTION

受体酪氨酸激酶（RTK）是跨膜蛋白， 将激素信号从细胞的外部传递到内部。 RTK的激活可以控制细胞代谢的许多方面， 生长和分化。 RTK信号不充分或不适当 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过度活跃的信号传导引起的癌），和 发育异常（如先天性巨结肠， RET RTK的信号不足）。 拟议研究的目的 是研究RTKs如何以生化方式控制细胞功能。 我们通过研究特定RTK的动作来解决这个问题， 果蝇的sevenless基因的产物 我们选择 研究sevenless，因为有能力执行遗传和 生物化学研究很难或不可能进行 在脊椎动物中。 无七RTK的激活充当开关， 果蝇眼睛的每个亚单位内的单个细胞发育为 感光细胞 我们的方法是确定 通过表征减弱信号传导通路的突变， 七号信令 我们已经证明了三种蛋白质的活性 （开瓶器，七个女儿和残疾人）是必不可少的， 有效诱导感光细胞发育。 我们的结果 已经表明失活的是激酶活性的可能底物 七少。 Corkscrew编码蛋白酪氨酸磷酸酶， 我们已经证明通过去磷酸化sevenless的女儿， 蛋白 拟议研究的目标是进一步表征 通过：1）生物化学和遗传 七少子的调控及作用探讨 在sevenless信号传导期间，2）进一步的分子表征 基因的产品与开瓶器和女儿的合作 在sevenless信号传导期间sevenless，和3）生化研究 残疾人功能。 由于RTKs下游的生化途径 在苍蝇和人类之间是高度保守的，我们希望一个更完整的 对sevenless信令的理解将为 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.