Hopkins, S;
Linderoth, E;
Hantschel, O;
Suarez-Henriques, P;
Pilia, G;
Kendrick, H;
Smalley, MJ;
... Ferby, I; + view all
(2012)
Mig6 is a sensor of EGF receptor inactivation that directly activates c-Abl to induce apoptosis during epithelial homeostasis.
Developmental Cell
, 23
(3)
547 - 559.
10.1016/j.devcel.2012.08.001.
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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.
| Type: | Article |
|---|---|
| Title: | Mig6 is a sensor of EGF receptor inactivation that directly activates c-Abl to induce apoptosis during epithelial homeostasis. |
| Location: | US |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.devcel.2012.08.001 |
| Publisher version: | http://dx.doi.org/10.1016/j.devcel.2012.08.001 |
| Language: | English |
| Additional information: | This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. PMCID: PMC3657149 |
| Keywords: | Adaptor Proteins, Signal Transducing, Animals, Apoptosis, Cells, Cultured, Epithelial Cells, HEK293 Cells, Homeostasis, Humans, Mice, Mice, Inbred BALB C, Mice, Knockout, Proto-Oncogene Proteins c-abl, Receptor, Epidermal Growth Factor |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1399223 |
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