Department of Biochemistry & Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia.
Cell Cycle and Development Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, 3002, Australia.
J Cell Sci. 2024 Feb 15;137(4). doi: 10.1242/jcs.261917. Epub 2024 Feb 16.
The tumour suppressor, Lethal (2) giant larvae [Lgl; also known as L(2)gl], is an evolutionarily conserved protein that was discovered in the vinegar fly Drosophila, where its depletion results in tissue overgrowth and loss of cell polarity. Lgl links cell polarity and tissue growth through regulation of the Notch and the Hippo signalling pathways. Lgl regulates the Notch pathway by inhibiting V-ATPase activity via Vap33. How Lgl regulates the Hippo pathway was unclear. In this current study, we show that V-ATPase activity inhibits the Hippo pathway, whereas Vap33 acts to activate Hippo signalling. Vap33 physically and genetically interacts with the actin cytoskeletal regulators RtGEF (Pix) and Git, which also bind to the Hippo protein (Hpo) and are involved in the activation of the Hippo pathway. Additionally, we show that the ADP ribosylation factor Arf79F (Arf1), which is a Hpo interactor, is involved in the inhibition of the Hippo pathway. Altogether, our data suggest that Lgl acts via Vap33 to activate the Hippo pathway by a dual mechanism: (1) through interaction with RtGEF, Git and Arf79F, and (2) through interaction and inhibition of the V-ATPase, thereby controlling epithelial tissue growth.
肿瘤抑制因子 Lethal（2） giant larvae [Lgl; 也称为 L(2)gl] 是一种进化上保守的蛋白质，最初在醋蝇果蝇中发现，其缺失会导致组织过度生长和细胞极性丧失。Lgl 通过调节 Notch 和 Hippo 信号通路将细胞极性和组织生长联系起来。Lgl 通过抑制 V-ATPase 活性来调节 Notch 通路，而 Vap33 通过抑制 V-ATPase 活性来抑制 V-ATPase 活性。Lgl 如何调节 Hippo 通路尚不清楚。在本研究中，我们表明 V-ATPase 活性抑制 Hippo 通路，而 Vap33 则激活 Hippo 信号。Vap33 与肌动蛋白细胞骨架调节因子 RtGEF (Pix) 和 Git 发生物理和遗传相互作用，它们也与 Hippo 蛋白 (Hpo) 结合，并参与 Hippo 通路的激活。此外，我们还表明，ADP 核糖基化因子 Arf79F (Arf1)，它是 Hpo 的相互作用因子，参与抑制 Hippo 通路。总的来说，我们的数据表明，Lgl 通过 Vap33 激活 Hippo 通路，其机制有二：（1）通过与 RtGEF、Git 和 Arf79F 相互作用，（2）通过与 V-ATPase 相互作用并抑制其活性，从而控制上皮组织生长。
