Ihog家族蛋白对整联蛋白功能的调节机制研究

Integrins are well conserved in metazoan, mediating cell adhesion and the subsequent signal transduction for various cellular processes, and thus playing essential roles from embryonic development, organogenesis to tissue homeostasis maintenance, and being highly relevant to human diseases such as cancers and autoimmune diseases. Although our knowledge of the focal adhesion formation and the involved integrin associated proteins is ever expanding, the current understanding of the mechanisms on how the integrin-mediated focal adhesion is regulated, a key and fundamental question in biology, is way from satisfactory. Using Drosophila melanogaster as a model system, we discovered that the loss of Ihog proteins, the Patch co-receptors in Hedgehog signaling, leads to wing blister, a typical phenotype for integrin defects in Drosophila. In this proposal, we will further demonstrate the involvement of Ihog proteins in integrin biology and mechanistically explore their regulatory roles on integrin activation, clustering and the eventual focal adhesion formation from tissue/cellular level and molecular level. The outcomes of this project will improve the understanding of the biology underlying the integrin-mediated focal adhesion, providing new insights into the diagnosis and medical treatment of the related human diseases.

整联蛋白在后口动物中是高度保守的，介导细胞黏着以进行信号转导，参与众多细胞过程，在胚胎发育、组织形成和稳态维持中起至关重要的作用，与癌症、自身免疫病等有密切关系。尽管对整联蛋白介导的黏着斑形成及相关蛋白已有大量研究，但“整联蛋白介导的细胞黏着是如何被调节的” 这个关键的基础生物学问题仍有许多机制尚未明确。申请人以果蝇为模式生物，发现Hedgehog信号转导中作为受体Ptc辅受体的Ihog家族蛋白的功能丧失能导致果蝇中整联蛋白缺陷的经典“膜泡”翅膀。本项目以此为基础，提出Ihog家族蛋白参与整联蛋白介导的细胞过程，从组织/细胞水平以及分子水平研究其对整联蛋白介导的细胞黏着的调节作用。本项目的实施，将有助于加深对整联蛋白介导的细胞黏着这一生物学过程的理解，为相关的人类疾病的诊断和治疗提供重要的理论基础和实践指导。

整联蛋白的表达会聚向于黏着斑，但在生理条件下这个生物学过程的调控机制却并不清楚。Ihog家族蛋白是一类进化上保守的蛋白，作为辅受体参与到Hedgehog信号转导，作为反式同源粘附分子介导细胞之间的相互作用。Ihog家族蛋白是否还参与其他的细胞粘附过程则还不明晰。本项目以果蝇为模式生物，发现Ihog家族蛋白也在整联蛋白介导的黏着斑中发挥作用。果蝇中Ihog家族蛋白缺陷导致的膜泡翅和胚胎的圆形肌肉表型都是典型的果蝇中的整联蛋白缺陷表型。我们进一步证明Ihog家族蛋白能和整联蛋白发生相互作用，它们之间的相互作用是依赖于其胞外区。Ihog家族蛋白的缺陷影响了整联蛋白的细胞膜分布。我们还通过在果蝇胚胎中表达Ihog家族中的哺乳动物同源蛋白Boc可以拯救由果蝇Ihog家族蛋白缺陷所造成的表型，证实了Ihog家族蛋白参与调控整联蛋白水平聚向上的功能是进化上保守的。