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Targeting of Ras-mediated FGF signaling suppresses Pten-deficient skin tumor.

TitleTargeting of Ras-mediated FGF signaling suppresses Pten-deficient skin tumor.
Publication TypeJournal Article
Year of Publication2016
AuthorsMathew G, Hannan A, Hertzler-Schaefer K, Wang F, Feng G-S, Zhong J, Zhao JJ, Downward J, Zhang X
JournalProc Natl Acad Sci U S A
Volume113
Issue46
Pagination13156-13161
Date Published2016 Nov 15
ISSN1091-6490
Abstract

Deficiency in PTEN (phosphatase and tensin homolog deleted on chromosome 10) is the underlying cause of PTEN hamartoma tumor syndrome and a wide variety of human cancers. In skin epidermis, we have previously identified an autocrine FGF signaling induced by loss of Pten in keratinocytes. In this study, we demonstrate that skin hyperplasia requires FGF receptor adaptor protein Frs2α and tyrosine phosphatase Shp2, two upstream regulators of Ras signaling. Although the PI3-kinase regulatory subunits p85α and p85β are dispensable, the PI3-kinase catalytic subunit p110α requires interaction with Ras to promote hyperplasia in Pten-deficient skin, thus demonstrating an important cross-talk between Ras and PI3K pathways. Furthermore, genetic and pharmacological inhibition of Ras-MAPK pathway impeded epidermal hyperplasia in Pten animals. These results reveal a positive feedback loop connecting Pten and Ras pathways and suggest that FGF-activated Ras-MAPK pathway is an effective therapeutic target for preventing skin tumor induced by aberrant Pten signaling.

DOI10.1073/pnas.1604450113
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID27799550
PubMed Central IDPMC5135310
Grant ListR01 EY022409 / EY / NEI NIH HHS / United States
R01 EY017061 / EY / NEI NIH HHS / United States
R01 CA176012 / CA / NCI NIH HHS / United States
R01 CA172461 / CA / NCI NIH HHS / United States
P30 AR044535 / AR / NIAMS NIH HHS / United States
R01 CA188506 / CA / NCI NIH HHS / United States
P30 EY019007 / EY / NEI NIH HHS / United States
R01 EY025933 / EY / NEI NIH HHS / United States
R01 EY018868 / EY / NEI NIH HHS / United States