The Hippo pathway is a master regulator of tissue homeostasis and organ size. NF2 is a well-established tumor suppressor, and loss of NF2 severely compromises Hippo pathway activity. However, the precise mechanism of how NF2 mediates upstream signals to regulate the Hippo pathway is not clear. Here we report that, in mammalian cells, NF2's lipid-binding ability is critical for its function in activating the Hippo pathway in response to osmotic stress. Mechanistically, osmotic stress induces PI(4,5)P2 plasma membrane enrichment by activating the PIP5K family, allowing for NF2 plasma membrane recruitment and subsequent downstream Hippo pathway activation. An NF2 mutant deficient in lipid binding is unable to activate the Hippo pathway in response to osmotic stress, as measured by LATS and YAP phosphorylation. Our findings identify the PIP5K family as novel regulators upstream of Hippo signaling, and uncover the importance of phosphoinositide dynamics, specifically PI(4,5)P2, in Hippo pathway regulation.

中文翻译：

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磷酸肌醇和 NF2 在 Hippo 通路调控中的关键作用。

Hippo 通路是组织稳态和器官大小的主要调节器。NF2 是一种公认​​的肿瘤抑制因子，NF2 的缺失会严重损害 Hippo 通路的活性。然而，NF2如何介导上游信号来调节Hippo通路的确切机制尚不清楚。在这里，我们报告说，在哺乳动物细胞中，NF2 的脂质结合能力对其激活 Hippo 通路以响应渗透压的功能至关重要。从机制上讲，渗透压通过激活 PIP5K 家族诱导 PI(4,5)P2 质膜富集，从而允许 NF2 质膜募集和随后的下游 Hippo 通路激活。脂质结合缺陷的 NF2 突变体无法激活 Hippo 通路以响应渗透压，如通过 LATS 和 YAP 磷酸化所测量的。