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Growth inhibition mediated by Hippo (Hpo) signaling is essential for tissue growth and organ size control in Drosophila. However, the cellular mechanism by which the core components like Mob as tumor suppressor (Mats) and Warts (Wts) protein kinase are activated is poorly understood. In this work, we found that the endogenous Mats is located at the plasma membrane in developing tissues. Membrane targeting constitutively activates Mats to promote apoptosis and reduce cell proliferation, which leads to reduced tissue growth and organ size. Moreover, the ability of membrane-targeted Mats to inhibit tissue growth required the wts gene activity and Wts kinase activity was increased by the activated Mats in developing tissues. Consistent with the idea that Mats is a key component of the Hpo pathway, Mats is required and sufficient to regulate Yki nuclear localization. These results support a model in which the plasma membrane is an important site of action for Mats tumor suppressor to control tissue growth and organ size. 相似文献
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Tissue growth and organ size are determined by coordinated cell proliferation and apoptosis in development. Recent studies have demonstrated that Hippo (Hpo) signaling plays a crucial role in coordinating these processes by restricting cell proliferation and promoting apoptosis. Here we provide evidence that the Mob as tumor suppressor protein, Mats, functions as a key component of the Hpo signaling pathway. We found that Mats associates with Hpo in a protein complex and is a target of the Hpo serine/threonine protein kinase. Mats phosphorylation by Hpo increases its affinity with Warts (Wts)/large tumor suppressor (Lats) serine/threonine protein kinase and ability to upregulate Wts catalytic activity to target downstream molecules such as Yorkie (Yki). Consistently, our epistatic analysis suggests that mats acts downstream of hpo. Coexpression analysis indicated that Mats can indeed potentiate Hpo-mediated growth inhibition in vivo. Our results support a model in which Mats is activated by Hpo through phosphorylation for growth inhibition, and this regulatory mechanism is conserved from flies to mammals. 相似文献
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Jin Y Dong L Lu Y Wu W Hao Q Zhou Z Jiang J Zhao Y Zhang L 《The Journal of biological chemistry》2012,287(8):5784-5796
The Hippo (Hpo) signaling pathway controls organ size by regulating the balance between cell proliferation and apoptosis. Although the Hpo function is conserved, little is known about the mechanism of how its kinase activity is regulated. Based on structural information, we performed mutation-function analysis and provided in vitro and in vivo evidence that Hpo activation requires proper dimerization of its N-terminal kinase domain as well as the C-terminal SARAH domain. Hpo carrying point mutation M242E can still dimerize, yet the dimers formed between intermolecular kinase domains were altered in conformation. As a result, autophosphorylation of Hpo at Thr-195 was blocked, and its kinase activity was abolished. In contrast, Hpo carrying I634D, a single mutation introduced in the Hpo C-terminal SARAH domain, disrupted the dimerization of the SARAH domain, leading to reduced Hippo activity. We also find that the Hpo C-terminal half contains two nuclear export signals that promote cytoplasmic localization and activity of Hpo. Taken together, our results suggest that dimerization and nucleocytoplasmic translocation of Hpo are crucial for its biological function and indicate that a proper dimer conformation of the kinase domain is essential for Hpo autophosphorylation and kinase activity. 相似文献