Signalling mechanisms of the ShcD adaptor protein

信号转导是多细胞生物的一个中心过程，它允许细胞之间和细胞内的信息线索交换。这些信号被细胞内调节复杂生化事件的有组织的蛋白质相互作用网络解释，最终转化为生物反应，如生长、迁移、分化和生存。细胞已经进化出一种巨大的能力，通过形成不同的蛋白质复合物，选择性地激活特定的下游途径。因此，了解这些相互作用的分子基础是生物学中的一个重大挑战。细胞内接头蛋白的Shc家族为研究选择性和特异性问题提供了独特的机会。这些蛋白的功能是将基于磷酸酪氨酸的信号从细胞表面受体传递给各种效应蛋白，它们在心血管和神经发育中起关键作用。有趣的是，Shc家族的复杂性已经从苍蝇中的一个基因增加到哺乳动物中的几个基因，我们最近表征了第四个哺乳动物同源基因ShcD。我们发现这种接头在Shc蛋白的表达模式和与结合靶点相关联的能力中是独一无二的，这支持了在进化过程中发生的Shc功能复杂多样化的观点。结合生物化学、细胞和遗传学的方法，我们建议鉴定与ShcD相关的分子成分和生物学功能。本研究的目的是剖析Shc蛋白信号传导模式，揭示信号转导的特异性是从单一的简单接头蛋白家族进化而来的机制。我们的发现也可能为解释细胞通讯的扰动如何导致细胞功能的改变提供机制上的见解。

Signal transduction is a central process in multicellular organisms that allows for the exchange of informational cues between and within cells. These cues are interpreted by organized networks of protein interactions inside the cell which regulate complex biochemical events, ultimately converting them into biological responses such as growth, migration, differentiation and survival. Cells have evolved a tremendous ability to selectively activate specific downstream pathways, through formation of distinct protein complexes. Understanding the molecular basis of these interactions is therefore a significant challenge in biology. The Shc family of intracellular adaptor proteins provides a unique opportunity to investigate the questions of selectivity and specificity. These proteins function to relay phosphotyrosine-based signals from cell surface receptors to various effector proteins, and they play critical roles in cardiovascular and neural development. Intriguingly, the Shc family has increased in complexity from one gene in flies to several in mammals, and we have recently characterized a fourth mammalian homolog, ShcD. We have found that this adaptor is unique among Shc proteins in its expression pattern and its ability to associate with binding targets, supporting the notion that elaborate diversification of Shc functions has occurred during evolution. Using a combination of biochemical, cellular and genetic approaches, we propose to identify the molecular components and biological functions associated with ShcD. The goal of this study is to dissect the Shc protein signaling paradigm to reveal the mechanisms by which specificity in signal transduction has evolved from a single family of simple adaptor proteins. Our findings may also provide mechanistic insight to explain how perturbations in cellular communication can lead to altered cell function.