作为发育、器官大小、组织稳态和癌症的关键调节因子，Hippo 通路受到各种生长相关信号事件的严格调节。其中，能量应激激活Hippo通路抑制其下游效应子YAP1。我们最近的工作报道了 Hippo 通路在响应能量应激时促进巨自噬/自噬和细胞存活的独立于 YAP1 的作用，这一过程由 Hippo 激酶 MAP4K2 介导。 MAP4K2 在 S87 处与 MAP1LC3A/LC3A 相互作用并磷酸化 MAP1LC3A/LC3A，进而通过 RAB3GAP-RAB18 轴驱动自噬体-溶酶体融合。能量应激通过减少 MAP4K2 与河马磷酸酶复合物 STRIPAK 成分 STRN4 的关联来激活 MAP4K2。此外，MAP4K2在头颈癌中高表达，而MAP4K2及其介导的自噬是头颈癌发生所必需的。总而言之，我们的研究不仅揭示了 Hippo 通路在能量应激反应中的非典型作用，而且还表明 Hippo 激酶 MAP4K2 作为头颈癌治疗的潜在治疗靶点。

As a key regulator of development, organ size, tissue homeostasis and cancer, the Hippo pathway is tightly regulated by various growth-related signaling events. Among them, energy stress activates the Hippo pathway to inhibit its downstream effector YAP1. Our recent work reported a YAP1-independent role of the Hippo pathway in promoting macroautophagy/autophagy and cell survival in response to energy stress, a process mediated by Hippo kinase MAP4K2. MAP4K2 interacts with and phosphorylates MAP1LC3A/LC3A at S87, which in turn drives autophagosome-lysosome fusion via the RAB3GAP-RAB18 axis. Energy stress activates MAP4K2 by reducing its association with the Hippo phosphatase complex STRIPAK component STRN4. Moreover, MAP4K2 is highly expressed in head and neck cancer, while MAP4K2 and its mediated autophagy are required for head and neck cancer development. Taken together, our study not only reveals a noncanonical role of the Hippo pathway in energy stress response, but also suggests Hippo kinase MAP4K2 as a potential therapeutic target for head and neck cancer treatment.