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

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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URL: https://www.ncbi.nlm.nih.gov/pubmed/27799550
DOI: 10.1073/pnas.1604450113

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: http://repository.cshl.edu/id/eprint/33959

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