title: EGF augments TGFβ-induced epithelial-mesenchymal transition by promoting SHP2 binding to GAB1.
abstract: In many epithelial cells, epidermal growth factor (EGF) augments the epithelial-mesenchymal transition (EMT) that occurs when cells are treated with transforming growth factor β (TGFβ). We demonstrate that this augmentation requires activation of SH2 domain-containing phosphatase-2 (SHP2; also known as PTPN11), a proto-oncogene. In lung and pancreatic cancer cell lines, reductions in E-cadherin expression, increases in vimentin expression and increases in cell scatter rates were larger when cells were treated with TGFβ and EGF versus TGFβ or EGF alone. SHP2 knockdown promoted epithelial characteristics basally and antagonized EMT in response to TGFβ alone or in combination with EGF. Whereas EGF promoted SHP2 binding to tyrosine phosphorylated GAB1, which promotes SHP2 activity, TGFβ did not induce SHP2 association with phosphotyrosine-containing proteins. Knockdown of endogenous SHP2 and reconstitution with an SHP2 mutant with impaired phosphotyrosine binding ability eliminated the EGF-mediated EMT augmentation that was otherwise restored with wild-type SHP2 reconstitution. These results demonstrate roles for basal and ligand-induced SHP2 activity in EMT and further motivate efforts to identify specific ways to inhibit SHP2, given the role of EMT in tumor dissemination and chemoresistance.
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Janine M
authors.initials: JM
authors.lastname: Buonato
authors.affiliation: Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Ingrid S
authors.initials: IS
authors.lastname: Lan
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, PA 19104, USA Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA mlazzara@seas.upenn.edu.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Lazzara
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D015153:Blotting, Western; D002460:Cell Line; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D006801:Humans; D047468:Immunoprecipitation; D011485:Protein Binding / Q000187:drug effects; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C098587:GAB1 protein, human; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016212:Transforming Growth Factor beta; D004815:Epidermal Growth Factor; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11
keywords: Carcinoma; Cell scatter; E-cadherin; Epidermal growth factor receptor (EGFR); Extracellular signal-regulated kinase (ERK); Vimentin