STRUCTURE AND FUNCTION OF THE BETA CYTOPLASMIC DOMAINS

整合素的细胞质结构域提供了一个重要的联系 胞外区和细胞质中的配体结合序列 负责将信号传递到细胞内通路的组件。 对于可激活的整合素，如alphaIIb/beta3，细胞质结构域 也为来自细胞质途径的由内向外的信号提供了链接 胞外配体结合序列。尽管如此， 整合素作为信号中介受体的识别，确切的性质 在这些信号中，识别那些直接产生的信号 是整合素和由整合素二次产生的整合素，以及 这些信号之间的关系仍不确定。总体目标 该项目的目的是识别相互作用的细胞质结构域序列 并调节整合素相关信号，并使用该结构 信息，以更好地了解信号的性质。 使用定点突变和多肽方法，最小序列 在与α-肌动蛋白，talin， 纽蛋白和整合素相关的焦点粘连的其他成分将 被映射。与局灶性黏附相互作用的细胞质结构域序列 蛋白激酶(pp125/FAK)和帕西林及其相互作用的作用 在焦点粘连的形成和整合素的激活上也会 下定决心。酪氨酸残基的磷酸化在血管内皮细胞中的潜在作用 β3的胞质尾部及其磷酸化在蛋白合成中的作用 我们将研究信号调解。最后，需要的序列是 整合素与MAP激酶各组分的相互作用和反应 H-ras和R-ras对整合素活化的调节 被指认出来。

The cytoplasmic domains of integrins provide an important link between the ligand binding sequences in the extracellular domain and cytoplasmic components responsible for transducing signals to intracellular pathways. For activatable integrins such as alphaIIb/beta3, the cytoplasmic domains also provide a link for inside-out signals from cytoplasmic pathways to the extracellular ligand binding sequences. Despite this increased recognition of integrins as signal mediating receptors, the precise nature of these signals, the identification of those that are generated directly be integrins and those that are secondarily generated by integrins, and the relationship between these signals remain uncertain. The overall aim of this project is to identify cytoplasmic domain sequences which interact with and mediate integrin-associated signals and to use this structural information to gain a better understanding of the nature of the signals. Using site-directed mutagenesis and peptide approaches, minimal sequences in the beta 3 cytoplasmic domain which interact with alpha-actinin, talin, vinculin, and other components of integrin-associated focal adhesions will be mapped. Cytoplasmic domain sequences which interact with focal adhesion kinase (pp125/FAK) and paxillin and the role that these interactions have in focal adhesion formation and integrin activation will also be determined. The potential role of phosphorylation of tyrosine residues in the cytoplasmic tail of beta 3 and the role that phosphorylation plays in signal mediation will be examined. Finally, sequences required for the interaction and responses of integrins to components of the MAP kinase cascade and the regulation of integrin activation by H-ras and R-ras will be identified.