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

Grinu Mathew, Abdul Hannan, Kristina Hertzler-Schaefer, Fen Wang, Gen Sheng Feng, Jian Zhong, Jean J. Zhao, Julian Downward, Xin Zhang

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


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 crosstalk 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.

Original languageEnglish (US)
Pages (from-to)13156-13161
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number46
StatePublished - Nov 15 2016


  • Erk
  • FGF
  • Pten
  • Ras
  • Skin

ASJC Scopus subject areas

  • General


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