1. Functional annotation of the Hippo pathway somatic mutations in human cancers.
- Author
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Han H, Huang Z, Xu C, Seo G, An J, Yang B, Liu Y, Lan T, Yan J, Ren S, Xu Y, Xiao D, Yan JK, Ahn C, Fishman DA, Meng Z, Guan KL, Qi R, Luo R, and Wang W
- Subjects
- Humans, Mutation, Missense, Neurofibromin 2 genetics, Neurofibromin 2 metabolism, Loss of Function Mutation, Cell Line, Tumor, Animals, Head and Neck Neoplasms genetics, Head and Neck Neoplasms metabolism, Head and Neck Neoplasms pathology, Mutation, Mice, Adaptor Proteins, Signal Transducing genetics, Adaptor Proteins, Signal Transducing metabolism, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases metabolism, Hippo Signaling Pathway genetics, Neoplasms genetics, Neoplasms metabolism, Neoplasms pathology, Signal Transduction genetics
- Abstract
The Hippo pathway is commonly altered in cancer initiation and progression; however, exactly how this pathway becomes dysregulated to promote human cancer development remains unclear. Here we analyze the Hippo somatic mutations in the human cancer genome and functionally annotate their roles in targeting the Hippo pathway. We identify a total of 85 loss-of-function (LOF) missense mutations for Hippo pathway genes and elucidate their underlying mechanisms. Interestingly, we reveal zinc-finger domain as an integral structure for MOB1 function, whose LOF mutations in head and neck cancer promote tumor growth. Moreover, the schwannoma/meningioma-derived NF2 LOF mutations not only inhibit its tumor suppressive function in the Hippo pathway, but also gain an oncogenic role for NF2 by activating the VANGL-JNK pathway. Collectively, our study not only offers a rich somatic mutation resource for investigating the Hippo pathway in human cancers, but also provides a molecular basis for Hippo-based cancer therapy., Competing Interests: Competing interests: K.-L.G. is a co-founder of and holds an equity interest in Vivace Therapeutics. The other authors declare no competing interests., (© 2024. The Author(s).)
- Published
- 2024
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