PXD031725

PXD031725 is an original dataset announced via ProteomeXchange.

Title	Domain-specific p53 mutants activate EGFR by distinct mechanisms exposing tissue-independent therapeutic vulnerabilities
Description	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.
HostingRepository	jPOST
AnnounceDate	2023-02-17
AnnouncementXML	Submission_2023-04-02_20:18:12.794.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Radoslaw Sobota
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	L-methionine sulfoxide; S-carboxamidomethyl-L-cysteine; alpha-amino acetylated residue; unknown modification; unknown modification; deamidated L-asparagine; deamidated L-glutamine
Instrument	instrument

Revision	Datetime	Status	ChangeLog Entry
0	2022-02-17 01:28:38	ID requested
1	2023-02-16 07:00:05	announced
⏵ 2	2023-04-02 20:18:13	announced	2023-04-03: Updated PubMed.

Ho TLF, Lee MY, Goh HC, Ng GYN, Lee JJH, Kannan S, Lim YT, Zhao T, Lim EKH, Phua CZJ, Lee YF, Lim RYX, Ng PJH, Yuan J, Chan DKH, Lieske B, Chong CS, Lee KC, Lum J, Cheong WK, Yeoh KG, Tan KK, Sobota RM, Verma CS, Lane DP, Tam WL, Venkitaraman AR, Domain-specific p53 mutants activate EGFR by distinct mechanisms exposing tissue-independent therapeutic vulnerabilities. Nat Commun, 14(1):1726(2023) [pubmed]

submitter keyword: p53, DNA binding domain, transactivation domain, PPI, TMT

Ashok R. Venkitaraman
lab head
Radoslaw Sobota
contact affiliation	IMCB A-STAR Singapore
dataset submitter

jPOST dataset URI

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.jpostdb.org/JPST001483/