Targeting of Ras-mediated FGF signaling suppresses Pten-deficient skin tumor.
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Embargo End Date
ICR Authors
Authors
Mathew, G
Hannan, A
Hertzler-Schaefer, K
Wang, F
Feng, G-S
Zhong, J
Zhao, JJ
Downward, J
Zhang, X
Hannan, A
Hertzler-Schaefer, K
Wang, F
Feng, G-S
Zhong, J
Zhao, JJ
Downward, J
Zhang, X
Document Type
Journal Article
Date
2016-11
Date Accepted
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.
Citation
Proceedings of the National Academy of Sciences of the United States of America, 2016, 113 (46), pp. 13156 - 13161
Source Title
Publisher
ISSN
0027-8424
eISSN
1091-6490
Collections
Research Team
Lung Cancer Group