title: Mig6 is a sensor of EGF receptor inactivation that directly activates c-Abl to induce apoptosis during epithelial homeostasis.
abstract: A fundamental aspect of epithelial homeostasis is the dependence on specific growth factors for cell survival, yet the underlying mechanisms remain obscure. We found an "inverse" mode of receptor tyrosine kinase signaling that directly links ErbB receptor inactivation to the induction of apoptosis. Upon ligand deprivation Mig6 dissociates from the ErbB receptor and binds to and activates the tyrosine kinase c-Abl to trigger p73-dependent apoptosis in mammary epithelial cells. Deletion of Errfi1 (encoding Mig6) and inhibition or RNAi silencing of c-Abl causes impaired apoptosis and luminal filling of mammary ducts. Mig6 activates c-Abl by binding to the kinase domain, which is prevented in the presence of epidermal growth factor (EGF) by Src family kinase-mediated phosphorylation on c-Abl-Tyr488. These results reveal a receptor-proximal switch mechanism by which Mig6 actively senses EGF deprivation to directly activate proapoptotic c-Abl. Our findings challenge the common belief that deprivation of growth factors induces apoptosis passively by lack of mitogenic signaling.
authors.affiliation: Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hopkins
authors.forename: Emma
authors.initials: E
authors.lastname: Linderoth
authors.forename: Oliver
authors.initials: O
authors.lastname: Hantschel
authors.forename: Paula
authors.initials: P
authors.lastname: Suarez-Henriques
authors.forename: Giulia
authors.initials: G
authors.lastname: Pilia
authors.forename: Howard
authors.initials: H
authors.lastname: Kendrick
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Smalley
authors.forename: Giulio
authors.initials: G
authors.lastname: Superti-Furga
authors.forename: Ingvar
authors.initials: I
authors.lastname: Ferby
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C475819:Errfi1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D066246:ErbB Receptors; D016315:Proto-Oncogene Proteins c-abl