title: FGFR and PTEN signaling interact during lens development to regulate cell survival.
abstract: Lens epithelial cells express many receptor tyrosine kinases (RTKs) that stimulate PI3K-AKT and RAS-RAF-MEK-ERK intracellular signaling pathways. These pathways ultimately activate the phosphorylation of key cellular transcription factors and other proteins that control proliferation, survival, metabolism, and differentiation in virtually all cells. Among RTKs in the lens, only stimulation of fibroblast growth factor receptors (FGFRs) elicits a lens epithelial cell to fiber cell differentiation response in mammals. Moreover, although the lens expresses three different Fgfr genes, the isolated removal of Fgfr2 at the lens placode stage inhibits both lens cell survival and fiber cell differentiation. Phosphatase and tensin homolog (PTEN), commonly known as a tumor suppressor, inhibits ERK and AKT activation and initiates both apoptotic pathways, and cell cycle arrest. Here, we show that the combined deletion of Fgfr2 and Pten rescues the cell death phenotype associated with Fgfr2 loss alone. Additionally, Pten removal increased AKT and ERK activation, above the levels of controls, in the presence or absence of Fgfr2. However, isolated deletion of Pten failed to stimulate ectopic fiber cell differentiation, and the combined deletion of Pten and Fgfr2 failed to restore differentiation-specific Aquaporin0 and DnaseIIβ expression in the lens fiber cells.
authors.affiliation: Department of Biology, Cell Molecular and Structural Biology Graduate Program, Miami University, Oxford, OH, USA.
authors.forename: Blake R
authors.initials: BR
authors.lastname: Chaffee
authors.affiliation: Department of Biology, Cell Molecular and Structural Biology Graduate Program, Miami University, Oxford, OH, USA.
authors.forename: Thanh V
authors.initials: TV
authors.lastname: Hoang
authors.affiliation: Department of Biology, Cell Molecular and Structural Biology Graduate Program, Miami University, Oxford, OH, USA.
authors.forename: Melissa R
authors.initials: MR
authors.lastname: Leonard
authors.affiliation: Department of Biology, Cell Molecular and Structural Biology Graduate Program, Miami University, Oxford, OH, USA.
authors.forename: Devin G
authors.initials: DG
authors.lastname: Bruney
authors.affiliation: Department of Biology, Cell Molecular and Structural Biology Graduate Program, Miami University, Oxford, OH, USA.
authors.forename: Brad D
authors.initials: BD
authors.lastname: Wagner
authors.affiliation: Department of Biology, Cell Molecular and Structural Biology Graduate Program, Miami University, Oxford, OH, USA.
authors.forename: Joseph Richard
authors.initials: JR
authors.lastname: Dowd
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, Department of Molecular Genetics, The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Leone
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, Department of Molecular Genetics, The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Ostrowski
authors.affiliation: Department of Biology, Cell Molecular and Structural Biology Graduate Program, Miami University, Oxford, OH, USA. Electronic address: Robinsm5@miamioh.edu.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Robinson
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D002470:Cell Survival / Q000502:physiology*; D007908:Lens, Crystalline / Q000196:embryology; D020935:MAP Kinase Signaling System; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D016755:Proto-Oncogene Proteins c-jun; D016159:Tumor Suppressor Protein p53; C496354:Fgfr2 protein, mouse; D051497:Receptor, Fibroblast Growth Factor, Type 2; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: Differentiation; FGF Receptor; Lens; PTEN; Survival