Department of Zoology, University of Wisconsin-Madison, 250 North Mills Street, Madison, WI 53706, USA.
Development. 2012 Apr;139(8):1498-508. doi: 10.1242/dev.070367. Epub 2012 Mar 7.
The giant Drosophila protocadherin Fat (Ft) affects planar cell polarity (PCP). Ft also inhibits the overgrowth of imaginal discs via the Hippo pathway, repressing the activity of the transcription co-factor Yorkie (Yki). Much of Ft activity is likely to be mediated by its intracellular domain (Ft ICD). However, the links between the Ft ICD and either PCP or Hippo activity are poorly understood, and the role of the Hippo pathway in PCP is ambiguous. We have performed a structure-function analysis of the Ft ICD. We found that the effects of the Ft ICD on PCP and the Hippo pathway are largely separable. Surprisingly, the domains required for PCP and Hippo activities do not map to any of the previously identified protein interaction domains, nor, with one exception, to the regions that are highly conserved in mammalian Fat4. We also found that the extracellular domain of Ft can act independently of the Ft ICD in PCP and can trigger dominant-negative and boundary effects on Hippo activity, probably via binding to the protocadherin Dachsous.
果蝇原钙黏蛋白 Fat（Ft）是一个影响平面细胞极性（PCP）的巨型蛋白。Ft 还通过 Hippo 通路抑制了成虫盘的过度生长，抑制了转录共因子 Yorkie（Yki）的活性。Ft 的大部分活性可能是通过其细胞内结构域（Ft ICD）介导的。然而，Ft ICD 与 PCP 或 Hippo 活性之间的联系还知之甚少，Hippo 通路在 PCP 中的作用也不清楚。我们对 Ft ICD 进行了结构-功能分析。我们发现，Ft ICD 对 PCP 和 Hippo 通路的影响在很大程度上是可以分离的。令人惊讶的是，PCP 和 Hippo 活性所必需的结构域既不在先前鉴定的任何蛋白相互作用结构域上，也不在在哺乳动物 Fat4 中高度保守的区域上。我们还发现，Ft 的细胞外结构域可以在 PCP 中独立于 Ft ICD 发挥作用，并可以通过与原钙黏蛋白 Dachsous 结合，触发 Hippo 活性的显性负效应和边界效应，可能是通过与原钙黏蛋白 Dachsous 结合来实现的。
