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

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

  • Nat Commun. 2023 Mar 28;14(1):1726. doi: 10.1038/s41467-023-37223-3.
Teresa Lai Fong Ho 1 2 May Yin Lee 3 Hui Chin Goh 2 Germaine Yi Ning Ng 4 Jane Jia Hui Lee 3 Srinivasaraghavan Kannan 5 Yan Ting Lim 6 7 Tianyun Zhao 6 7 Edwin Kok Hao Lim 3 Cheryl Zi Jin Phua 3 Yi Fei Lee 3 Rebecca Yi Xuan Lim 3 Perry Jun Hao Ng 3 Ju Yuan 3 Dedrick Kok Hong Chan 8 9 Bettina Lieske 9 10 Choon Seng Chong 9 10 Kuok Chung Lee 9 Jeffrey Lum 11 Wai Kit Cheong 9 Khay Guan Yeoh 12 Ker Kan Tan 9 10 Radoslaw M Sobota 6 7 Chandra S Verma 5 13 14 David P Lane 1 Wai Leong Tam 2 3 13 15 16 Ashok R Venkitaraman 17 18 19
Affiliations

Affiliations

  • 1 Disease Intervention Technology Lab (DITL), Institute of Molecular and Cell Biology, Agency for Science Technology and Research (A*STAR), Singapore, Singapore.
  • 2 Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
  • 3 Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
  • 4 Singapore Institute of Technology, Singapore, Singapore.
  • 5 Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
  • 6 Functional Proteomics Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
  • 7 SingMass - National Mass Spectrometry Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
  • 8 Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.
  • 9 Division of Colorectal Surgery, University Surgical Cluster, National University Health System, Singapore, Singapore.
  • 10 Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • 11 Department of Pathology, National University Health System, Singapore, Singapore.
  • 12 University Surgical Cluster, National University Health System, Singapore, Singapore.
  • 13 School of Biological Science, Nanyang Technological University, Singapore, Singapore.
  • 14 Department of Biological Science, National University of Singapore, Singapore, Singapore.
  • 15 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • 16 NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • 17 Disease Intervention Technology Lab (DITL), Institute of Molecular and Cell Biology, Agency for Science Technology and Research (A*STAR), Singapore, Singapore. arv22@nus.edu.sg.
  • 18 Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore. arv22@nus.edu.sg.
  • 19 NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. arv22@nus.edu.sg.
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.

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