title: 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: Department of Ophthalmology, Columbia University, New York, NY 10032.|Department of Pathology and Cell Biology, Columbia University, New York, NY 10032.
authors: Grinu
authors: G
authors: Mathew
authors: Department of Ophthalmology, Columbia University, New York, NY 10032.|Department of Pathology and Cell Biology, Columbia University, New York, NY 10032.
authors: Abdul
authors: A
authors: Hannan
authors: Department of Biology, University of North Carolina, Chapel Hill, NC 27599.
authors: Kristina
authors: K
authors: Hertzler-Schaefer
authors: Center for Cancer Biology and Nutrition, Institute of Biosciences and Technology, Texas A&M, Houston, TX 77030.
authors: Fen
authors: F
authors: Wang
authors: Department of Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093.|Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093.
authors: Gen-Sheng
authors: GS
authors: Feng
authors: Burke Medical Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, White Plains, NY 10605.
authors: Jian
authors: J
authors: Zhong
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115.|Department of Biochemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115.
authors: Jean J
authors: JJ
authors: Zhao
authors: Oncogene Biology Laboratory, The Francis Crick Institute, London WC2A 3LY, United Kingdom.
authors: Julian
authors: J
authors: Downward
authors: Department of Ophthalmology, Columbia University, New York, NY 10032; xz2369@columbia.edu.|Department of Pathology and Cell Biology, Columbia University, New York, NY 10032.
authors: Xin
authors: X
authors: Zhang
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
chemical_list: C488187:FRS2alpha protein, mouse; D008565:Membrane Proteins; D005346:Fibroblast Growth Factors; D020928:Mitogen-Activated Protein Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D018631:ras Proteins
keywords: Erk; FGF; Pten; Ras; skin