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.
journal_name
Proc Natl Acad Sci U S Aauthors
Mathew G,Hannan A,Hertzler-Schaefer K,Wang F,Feng GS,Zhong J,Zhao JJ,Downward J,Zhang Xdoi
10.1073/pnas.1604450113subject
Has Abstractpub_date
2016-11-15 00:00:00pages
13156-13161issue
46eissn
0027-8424issn
1091-6490pii
1604450113journal_volume
113pub_type
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