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

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.

• Authors: Grinu Mathew, Abdul Hannan, Kristina Hertzler-Schaefer, Fen Wang, Gen-Sheng Feng, Jian Zhong, Jean J Zhao, Julian Downward, Xin Zhang
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 113 Issue 46 Pg. 13156-13161 (11 15 2016) ISSN: 1091-6490 [Electronic] United States
• PMID: 27799550 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• FRS2alpha protein, mouse
• Membrane Proteins
• Fibroblast Growth Factors
• Mitogen-Activated Protein Kinases
• Protein Tyrosine Phosphatase, Non-Receptor Type 11
• Ptpn11 protein, mouse
• PTEN Phosphohydrolase
• Pten protein, mouse
• ras Proteins

Topics

• Animals
• Cells, Cultured
• Fibroblast Growth Factors (metabolism)
• Keratinocytes (metabolism)
• Membrane Proteins (metabolism)
• Mice, Transgenic
• Mitogen-Activated Protein Kinases (metabolism)
• PTEN Phosphohydrolase (deficiency, genetics, metabolism)
• Protein Tyrosine Phosphatase, Non-Receptor Type 11 (metabolism)
• Signal Transduction
• Skin (metabolism)
• Skin Neoplasms (metabolism)
• ras Proteins (metabolism)