EGFR Regulates the Hippo pathway by promoting the tyrosine phosphorylation of MOB1

Toshinori Ando,Zhiyong Wang,Kazuyo Ando,Daniela Elena Costea,Mara Gilardi,Hiroki Izumi,Nadia Arang,Yusuke Goto,Xiaodong Feng,J Silvio Gutkind

doi:10.1038/s42003-021-02744-4

Abstract

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.

Highlights

The Hippo pathway is frequently dysregulated in cancer, leading to the unrestrained activity of its downstream targets, Yes-associated protein (YAP)/transcriptional co-activator with PDZ binding motif (TAZ), and aberrant tumor growth
We show that EGFR activation leads to the phosphorylation of one of the core Hippo pathway components, MOB1 to inhibit large tumor suppressor 1 and 2 (LATS1/2) function resulting in YAP/TAZ activation in head and neck squamous cell carcinoma (HNSCC) cells independent of FAT1 alterations
We have recently reported that frequent FAT1 alterations contribute to YAP activation in HNSCC, many FAT1 wild type HNSCC cases exhibit nuclear YAP8, and as such, the mechanism of YAP activation in HNSCC, and other cancer types, may not yet be fully understood

Summary

Introduction

The Hippo pathway is frequently dysregulated in cancer, leading to the unrestrained activity of its downstream targets, YAP/TAZ, and aberrant tumor growth. It is still possible that other molecular events may control YAP activation in >65% of HNSCC cases that do not exhibit YAP1 or FAT1 genomic alterations, whose elucidation may help reveal new molecular mechanisms controlling the Hippo pathway in cancer In this regard, EGFR, one of the ERBB family tyrosine kinases, is amplified and highly overexpressed in HNSCC and lung squamous cell carcinoma, and mutated and activated in many cancer types including lung adenocarcinoma and glioblastoma[7,9,10,11]. We show that EGFR activation leads to the phosphorylation of one of the core Hippo pathway components, MOB1 to inhibit LATS1/2 function resulting in YAP/TAZ activation in HNSCC cells independent of FAT1 alterations. These findings contribute to the understanding of the mechanisms by which EGFR-driven signaling networks control YAP/ TAZ activation in normal cells and cancer, and support the therapeutic potential of inhibiting YAP/TAZ function in patients with cancers harboring EGFR alterations to enhance the response to EGFR targeted therapies, and prevent emergence of drug resistance

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