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

ABSTRACT: Mis-sense mutations affecting TP53 promote carcinogenesis both by inactivating its tumor suppressive functions, and by conferring aberrant pro-carcinogenic activities. We report here that mis-sense mutants in the p53 DNA-binding domain (DBD) and the transactivation domain (TAD) 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 patterns and induced distinct gene expression profiles. Combining mass spectrometry with drug compound screens, we identified EGFR as a major signaling factor that is stabilized by TAD and DBD mutants in the cytosolic and nuclear compartments respectively, in a tissue-independent manner. Mechanistically, 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 upregulation of c-Myc and Cyclin D1 levels. Therapeutically, the sensitivity of DBD mutants to EGFR inhibition is enhanced by increasing the affinity of EGFR for SHP1, while that of TAD mutants can be induced by concurrent inhibition of AKT, mTOR or PI3K signaling. Thus, our findings suggest that gain-of-function, mis-sense mutations affecting two different p53 domains promote carcinogenesis by enhancing EGFR signaling via distinctive mechanisms. Our findings imply that cancer cells bearing domain-specific mutations may have distinct and exploitable therapeutic vulnerabilities.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Ashok R. Venkitaraman

PROVIDER: PXD031725 | JPOST Repository | Fri Feb 17 00:00:00 GMT 2023

REPOSITORIES: jPOST

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			Action	DRS
	20190611_Human_UniProt.fasta	Fasta
	20210209_Teresa_p53IP_F14.raw	Raw
	20210209_Teresa_p53IP_F18.raw	Raw
	20210209_Teresa_p53IP_F21.raw	Raw
	20210209_Teresa_p53IP_F24.raw	Raw

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

Ho Teresa Lai Fong TLF Lee May Yin MY Goh Hui Chin HC Ng Germaine Yi Ning GYN Lee Jane Jia Hui JJH Kannan Srinivasaraghavan S Lim Yan Ting YT Zhao Tianyun T Lim Edwin Kok Hao EKH Phua Cheryl Zi Jin CZJ Lee Yi Fei YF Lim Rebecca Yi Xuan RYX Ng Perry Jun Hao PJH Yuan Ju J Chan Dedrick Kok Hong DKH Lieske Bettina B Chong Choon Seng CS Lee Kuok Chung KC Lum Jeffrey J Cheong Wai Kit WK Yeoh Khay Guan KG Tan Ker Kan KK Sobota Radoslaw M RM Verma Chandra S CS Lane David P DP Tam Wai Leong WL Venkitaraman Ashok R AR

Nature communications 20230328 1

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 exp ...[more]

PMID: 36977662

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