EGFR Regulates the Hippo pathway by promoting the tyrosine phosphorylation of MOB1.
EGFR Regulates the Hippo pathway by promoting the tyrosine phosphorylation of MOB1.
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EGFR通过促进MOB 1的酪氨酸磷酸化来调节Hippo通路。
DOI：
10.1038/s42003-021-02744-4
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发表时间：
2021-11-01
影响因子：
5.9
通讯作者：
Gutkind JS
中科院分区：
文献类型：
--
作者：
Ando T;Arang N;Wang Z;Costea DE;Feng X;Goto Y;Izumi H;Gilardi M;Ando K;Gutkind JS
河马途径在癌症中经常被失调，导致其下游靶点YAP/TAZ的不受限制的活动，以及肿瘤的异常生长。然而，在大多数癌症中导致YAP/TAZ激活的确切机制仍然知之甚少。对大量组织收集的分析显示，YAP在大多数头颈部鳞状细胞癌(HNSCC)中都有激活，但只有29.8%的HNSCC病例存在FAT1肿瘤抑制基因的基因改变，这可能是持续YAP信号的基础。EGFR在HNSCC和许多其他癌症中过度表达，但EGFR是否控制YAP的激活仍然知之甚少。在这里，我们发现EGFR激活HNSCC细胞中的YAP/TAZ，但不依赖于其典型的信号靶点，包括PI3K。在机制上，我们发现EGFR促进河马通路的核心成分MOB1的磷酸化，并促进LATS1/2的失活，而不依赖于MST1/2。转录分析表明，临床上的EGFR抑制剂erlotinib可以失活Yap/TAZ。值得注意的是，LATS1/2的缺失导致YAP/TAZ活性异常，使埃洛替尼对HNSCC和肺癌细胞产生耐药。我们的发现表明，EGFR-YAP/TAZ信号在携带EGFR改变的癌症中起着促进生长的作用，抑制YAP/TAZ与EGFR联合使用可能有利于预防治疗耐药和癌症复发。Ando等人在头颈部鳞状细胞癌细胞中发现，EGFR激活导致Hippo途径组件MOB1的磷酸化，从而抑制LATS1/2功能，导致YAP/TAZ激活。此外，EGFR靶向治疗抑制了YAP/TAZ，而LATS1/2介导的YAP/TAZ激活的缺失增加了治疗耐药性，从而为研究具有激活的EGFR的癌症的潜在耐药机制提供了洞察力。
The Hippo pathway is frequently dysregulated in cancer, leading to the unrestrained activity of its downstream targets, YAP/TAZ, and aberrant tumor growth. However, the precise mechanisms leading to YAP/TAZ activation in most cancers is still poorly understood. Analysis of large tissue collections revealed YAP activation in most head and neck squamous cell carcinoma (HNSCC), but only 29.8% of HNSCC cases present genetic alterations in the FAT1 tumor suppressor gene that may underlie persistent YAP signaling. EGFR is overexpressed in HNSCC and many other cancers, but whether EGFR controls YAP activation is still poorly understood. Here, we discover that EGFR activates YAP/TAZ in HNSCC cells, but independently of its typical signaling targets, including PI3K. Mechanistically, we find that EGFR promotes the phosphorylation of MOB1, a core Hippo pathway component, and the inactivation of LATS1/2 independently of MST1/2. Transcriptomic analysis reveals that erlotinib, a clinical EGFR inhibitor, inactivates YAP/TAZ. Remarkably, loss of LATS1/2, resulting in aberrant YAP/TAZ activity, confers erlotinib resistance on HNSCC and lung cancer cells. Our findings suggest that EGFR-YAP/TAZ signaling plays a growth-promoting role in cancers harboring EGFR alterations, and that inhibition of YAP/TAZ in combination with EGFR might be beneficial to prevent treatment resistance and cancer recurrence. Ando et al show in head and neck squamous cell carcinoma cells that EGFR activation leads to the phosphorylation of the Hippo pathway component, MOB1 to inhibit LATS1/2 function resulting in YAP/TAZ activation. Further, EGFR-targeting therapies suppress YAP/TAZ, and loss of LATS1/2-mediated YAP/TAZ activation confers therapy resistance, thus offering insights into potential drug resistance mechanisms in cancers with activated EGFR.
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影响因子：
64.8
作者：
Chang L;Azzolin L;Di Biagio D;Zanconato F;Battilana G;Lucon Xiccato R;Aragona M;Giulitti S;Panciera T;Gandin A;Sigismondo G;Krijgsveld J;Fassan M;Brusatin G;Cordenonsi M;Piccolo S
通讯作者：
Piccolo S
影响因子：
10.5
作者：
Meng Z;Moroishi T;Guan KL
通讯作者：
Guan KL
影响因子：
158.5
作者：
Lynch, TJ;Bell, DW;Haber, DA
通讯作者：
Haber, DA
影响因子：
16.6
作者：
Meng Z;Moroishi T;Mottier-Pavie V;Plouffe SW;Hansen CG;Hong AW;Park HW;Mo JS;Lu W;Lu S;Flores F;Yu FX;Halder G;Guan KL
通讯作者：
Guan KL
影响因子：
4.8
作者：
Jerhammar, Fredrik;Johansson, Ann-Charlotte;Roberg, Karin
通讯作者：
Roberg, Karin