Mathew, G., Hannan, A., Hertzler-Schaefer, K., Wang, F., Feng, G. S., Zhong, J., Zhao, J. J., Downward, J., Zhang, X. (November 2016) Targeting of Ras-mediated FGF signaling suppresses Pten-deficient skin tumor. Proc Natl Acad Sci U S A, 113 (46). pp. 13156-13161. ISSN 1091-6490 (Electronic)0027-8424 (Linking)
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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 Frs2alpha and tyrosine phosphatase Shp2, two upstream regulators of Ras signaling. Although the PI3-kinase regulatory subunits p85alpha and p85beta are dispensable, the PI3-kinase catalytic subunit p110alpha 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.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | Erk Fgf Pten Ras skin |
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > PTEN bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > fibroblast growth factor bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > G protein > Ras |
| CSHL Authors: | |
| Communities: | CSHL labs > Trotman lab |
| Depositing User: | Matt Covey |
| Date: | 15 November 2016 |
| Date Deposited: | 10 Jan 2017 20:48 |
| Last Modified: | 08 Nov 2017 19:08 |
| PMCID: | PMC5135310 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/33959 |
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