Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, P-2780-156 Oeiras, Portugal.
Development. 2011 Jun;138(11):2337-46. doi: 10.1242/dev.063545. Epub 2011 Apr 27.
The conserved Hippo tumor suppressor pathway is a key kinase cascade that controls tissue growth by regulating the nuclear import and activity of the transcription co-activator Yorkie. Here, we report that the actin-Capping Protein αβ heterodimer, which regulates actin polymerization, also functions to suppress inappropriate tissue growth by inhibiting Yorkie activity. Loss of Capping Protein activity results in abnormal accumulation of apical F-actin, reduced Hippo pathway activity and the ectopic expression of several Yorkie target genes that promote cell survival and proliferation. Reduction of two other actin-regulatory proteins, Cofilin and the cyclase-associated protein Capulet, cause abnormal F-actin accumulation, but only the loss of Capulet, like that of Capping Protein, induces ectopic Yorkie activity. Interestingly, F-actin also accumulates abnormally when Hippo pathway activity is reduced or abolished, independently of Yorkie activity, whereas overexpression of the Hippo pathway component expanded can partially reverse the abnormal accumulation of F-actin in cells depleted for Capping Protein. Taken together, these findings indicate a novel interplay between Hippo pathway activity and actin filament dynamics that is essential for normal growth control.
Hippo 肿瘤抑制通路是一条保守的信号通路，通过调控转录共激活因子 Yorkie 的核内输入和活性来控制组织生长。本文报道了肌动蛋白加帽蛋白αβ异二聚体（调控肌动蛋白聚合）通过抑制 Yorkie 活性也能抑制组织过度生长。加帽蛋白活性缺失会导致顶端 F-actin 异常积累，降低 Hippo 信号通路活性，引起 Yorkie 靶基因的异位表达，从而促进细胞存活和增殖。另外两种肌动蛋白调控蛋白——丝切蛋白和周期蛋白相关蛋白 Capulet 的缺失会导致 F-actin 异常积累，但只有 Capulet 的缺失（与加帽蛋白缺失一样）会诱导 Yorkie 活性的异位表达。有趣的是，当 Hippo 信号通路活性降低或失活时，F-actin 也会异常积累，这一过程与 Yorkie 活性无关，而过表达 Hippo 信号通路组件 expanded 可部分逆转因加帽蛋白缺失导致的 F-actin 异常积累。综上，这些结果表明 Hippo 信号通路活性和肌动蛋白丝动力学之间存在新的相互作用，这对正常的生长控制至关重要。
