SPTAN1/NUMB axis senses cell density to restrain cell growth and oncogenesis through Hippo signaling.
SPTAN1/NUMB axis senses cell density to restrain cell growth and oncogenesis through Hippo signaling.
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DOI：
10.1172/jci168888
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发表时间：
2023-10-16
影响因子：
15.9
通讯作者：
Zhou, Dawang
中科院分区：
文献类型：
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作者：
Su, Dongxue;Li, Yuxi;Zhang, Weiji;Gao, Huan;Cheng, Yao;Hou, Yongqiang;Li, Junhong;Ye, Yi;Lai, Zhangjian;Li, Zhe;Huang, Haitao;Li, Jiaxin;Li, Jinhuan;Cheng, Mengyu;Nian, Cheng;Wu, Na;Zhou, Zhien;Xing, Yunzhi;Zhao, Yu;Liu, He;Tang, Jiayu;Chen, Qinghua;Hong, Lixin;Li, Wengang;Peng, Zhihai;Zhao, Bin;Johnson, Randy L.;Liu, Pingguo;Hong, Wanjin;Chen, Lanfen;Zhou, Dawang
接触抑制的丧失是癌变过程中的关键步骤。河马-是相关蛋白(Hippo/YAP)途径是细胞密度依赖的细胞生长的重要调节因子。然而，河马信号如何在这种情况下感知细胞密度仍然难以捉摸。在这里，我们报道高细胞密度诱导质膜稳定蛋白SPTAN1的α链的磷酸化，招募Num1和Numb1/2，这进一步隔离在质膜上的微管亲和力调节蛋白(MARKs)，使它们不能被磷酸化和抑制河马不育的20样蛋白MST1和MST2(MST1/2)。WW45与MST1/2的相互作用因此得到加强，导致河马信号被激活，以阻断YAP的活性，从而抑制细胞接触。重要是，低细胞密度导致SPTAN1去磷酸化和胞浆定位，同时抑制MST1/2，从而激活YAP。此外，肝脏中Numb和WW45的双重KO导致明显的器官肿大和快速的肿瘤形成。有趣是，Numb亚型3和4具有截短的磷酸酪氨酸结合(PTB)结构域，因此不能与磷酸化的SPTAN1相互作用并激活MST1/2，它们在肝癌中选择性上调，与YAP激活相关。因此，我们揭示了SPTAN1/NUMB1/2轴作为细胞密度传感器，通过将外部细胞-细胞接触信号与细胞内河马信号耦合来抑制细胞生长和肿瘤发生。
The loss of contact inhibition is a key step during carcinogenesis. The Hippo–Yes-associated protein (Hippo/YAP) pathway is an important regulator of cell growth in a cell density–dependent manner. However, how Hippo signaling senses cell density in this context remains elusive. Here, we report that high cell density induced the phosphorylation of spectrin α chain, nonerythrocytic 1 (SPTAN1), a plasma membrane–stabilizing protein, to recruit NUMB endocytic adaptor protein isoforms 1 and 2 (NUMB1/2), which further sequestered microtubule affinity–regulating kinases (MARKs) in the plasma membrane and rendered them inaccessible for phosphorylation and inhibition of the Hippo kinases sterile 20–like kinases MST1 and MST2 (MST1/2). WW45 interaction with MST1/2 was thereby enhanced, resulting in the activation of Hippo signaling to block YAP activity for cell contact inhibition. Importantly, low cell density led to SPTAN1 dephosphorylation and NUMB cytoplasmic location, along with MST1/2 inhibition and, consequently, YAP activation. Moreover, double KO of NUMB and WW45 in the liver led to appreciable organ enlargement and rapid tumorigenesis. Interestingly, NUMB isoforms 3 and 4, which have a truncated phosphotyrosine-binding (PTB) domain and are thus unable to interact with phosphorylated SPTAN1 and activate MST1/2, were selectively upregulated in liver cancer, which correlated with YAP activation. We have thus revealed a SPTAN1/NUMB1/2 axis that acts as a cell density sensor to restrain cell growth and oncogenesis by coupling external cell-cell contact signals to intracellular Hippo signaling.