Domain-specific p53 mutants activate EGFR by distinct mechanisms exposing tissue-independent therapeutic vulnerabilities

Teresa Lai Fong Ho, May Yin Lee, Hui Chin Goh, Germaine Yi Ning Ng, Jane Jia Hui Lee, Srinivasaraghavan Kannan, Yan Ting Lim, Tianyun Zhao, Edwin Kok Hao Lim, Cheryl Zi Jin Phua, Yi Fei Lee, Rebecca Yi Xuan Lim, Perry Jun Hao Ng, Ju Yuan, Dedrick Kok Hong Chan, Bettina Lieske, Choon Seng Chong, Kuok Chung Lee, Jeffrey Lum, Wai Kit Cheong, Khay Guan Yeoh, Ker Kan Tan, Radoslaw M. Sobota, Chandra S. Verma, David P. Lane, Wai Leong Tam and Ashok R. Venkitaraman ()
Additional contact information
Teresa Lai Fong Ho: Agency for Science Technology and Research (A*STAR)
May Yin Lee: Technology and Research (A*STAR)
Hui Chin Goh: National University of Singapore
Germaine Yi Ning Ng: Singapore Institute of Technology
Jane Jia Hui Lee: Technology and Research (A*STAR)
Srinivasaraghavan Kannan: Technology and Research (A*STAR)
Yan Ting Lim: Agency for Science, Technology and Research (A*STAR)
Tianyun Zhao: Agency for Science, Technology and Research (A*STAR)
Edwin Kok Hao Lim: Technology and Research (A*STAR)
Cheryl Zi Jin Phua: Technology and Research (A*STAR)
Yi Fei Lee: Technology and Research (A*STAR)
Rebecca Yi Xuan Lim: Technology and Research (A*STAR)
Perry Jun Hao Ng: Technology and Research (A*STAR)
Ju Yuan: Technology and Research (A*STAR)
Dedrick Kok Hong Chan: University of Oxford
Bettina Lieske: National University Health System
Choon Seng Chong: National University Health System
Kuok Chung Lee: National University Health System
Jeffrey Lum: National University Health System
Wai Kit Cheong: National University Health System
Khay Guan Yeoh: University Surgical Cluster, National University Health System
Ker Kan Tan: National University Health System
Radoslaw M. Sobota: Agency for Science, Technology and Research (A*STAR)
Chandra S. Verma: Technology and Research (A*STAR)
David P. Lane: Agency for Science Technology and Research (A*STAR)
Wai Leong Tam: National University of Singapore
Ashok R. Venkitaraman: Agency for Science Technology and Research (A*STAR)

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract Mis-sense mutations affecting TP53 promote carcinogenesis both by inactivating tumor suppression, and by conferring pro-carcinogenic activities. We report here that p53 DNA-binding domain (DBD) and transactivation domain (TAD) mis-sense mutants unexpectedly activate pro-carcinogenic epidermal growth factor receptor (EGFR) signaling via distinct, previously unrecognized molecular mechanisms. DBD- and TAD-specific TP53 mutants exhibited different cellular localization and induced distinct gene expression profiles. In multiple tissues, EGFR is stabilized by TAD and DBD mutants in the cytosolic and nuclear compartments respectively. TAD mutants promote EGFR-mediated signaling by enhancing EGFR interaction with AKT via DDX31 in the cytosol. Conversely, DBD mutants maintain EGFR activity in the nucleus, by blocking EGFR interaction with the phosphatase SHP1, triggering c-Myc and Cyclin D1 upregulation. Our findings suggest that p53 mutants carrying gain-of-function, mis-sense mutations affecting two different domains form new protein complexes that promote carcinogenesis by enhancing EGFR signaling via distinctive mechanisms, exposing clinically relevant therapeutic vulnerabilities.

Date: 2023
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DOI: 10.1038/s41467-023-37223-3

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