Mig6 Is a Sensor of EGF Receptor Inactivation that Directly Activates c-Abl to Induce Apoptosis during Epithelial Homeostasis
dc.contributor.author | Hopkins, S | |
dc.contributor.author | Linderoth, E | |
dc.contributor.author | Hantschel, O | |
dc.contributor.author | Suarez-Henriques, P | |
dc.contributor.author | Pilia, G | |
dc.contributor.author | Kendrick, H | |
dc.contributor.author | Smalley, MJ | |
dc.contributor.author | Superti-Furga, G | |
dc.contributor.author | Ferby, I | |
dc.date.accessioned | 2018-08-08T09:22:03Z | |
dc.date.issued | 2012-09-11 | |
dc.identifier | 3 | |
dc.identifier.citation | DEVELOPMENTAL CELL, 2012, 23 pp. 547 - 559 | |
dc.identifier.issn | 1534-5807 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/2295 | |
dc.identifier.eissn | 1878-1551 | |
dc.identifier.doi | 10.1016/j.devcel.2012.08.001 | |
dc.description.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. | |
dc.format.extent | 547 - 559 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | CELL PRESS | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.title | Mig6 Is a Sensor of EGF Receptor Inactivation that Directly Activates c-Abl to Induce Apoptosis during Epithelial Homeostasis | |
dc.type | Journal Article | |
rioxxterms.versionofrecord | 10.1016/j.devcel.2012.08.001 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2012-09-11 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | DEVELOPMENTAL CELL | |
pubs.notes | affiliation: Ferby, I (Reprint Author), UCL, Wolfson Inst Biomed Res, Gower St, London WC1E 6BT, England. Hopkins, Sarah; Linderoth, Emma; Suarez-Henriques, Paula; Ferby, Ingvar, UCL, Wolfson Inst Biomed Res, London WC1E 6BT, England. Hantschel, Oliver; Superti-Furga, Giulio, Austrian Acad Sci, CeMM Ctr Mol Med, A-1090 Vienna, Austria. Pilia, Giulia; Ferby, Ingvar, Uppsala Univ, Ludwig Inst Canc Res, Sci Life Lab, S-75124 Uppsala, Sweden. Kendrick, Howard; Smalley, Matthew J., Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England. keywords-plus: GROWTH-FACTOR RECEPTOR; TYROSINE KINASE; NEGATIVE REGULATOR; CELLULAR-RESPONSE; CATALYTIC DOMAIN; SRC FAMILY; PHOSPHORYLATION; MORPHOGENESIS; HEPATOCYTES; INHIBITION research-areas: Cell Biology; Developmental Biology web-of-science-categories: Cell Biology; Developmental Biology author-email: [email protected] researcherid-numbers: Smalley, Matthew/M-7000-2015 Superti-Furga, Giulio/F-4755-2015 Hantschel, Oliver/H-4705-2013 Suarez-Henriques, Paula/E-2606-2015 orcid-numbers: Smalley, Matthew/0000-0001-9540-1146 Superti-Furga, Giulio/0000-0002-0570-1768 Hantschel, Oliver/0000-0001-8569-8169 funding-acknowledgement: AICR; BBSRC; Royal Society; Ludwig Institute for Cancer Research; Institut de Recherches Servier, France; Breakthrough Breast Cancer funding-text: We would like to acknowledge Michael Way (London Research Institute, Cancer Research UK, London) and Staffan Johansson (Uppsala University, Sweden) for providing MEF cell lines, Aive Agren for technical assistance (Ludwig Institute for Cancer Research, Uppsala), and John Hickman (Institut de Recherches Servier, France), Michael Way, Taija Makinen (London Research Institute, Cancer Research UK, London), and Sir Salvador Moncada (Wolfson Institute for Biomedical Research, UCL, London) for critically reading the manuscript. S.H. and E.L. performed most of the experimental work and Aive Agren, G.P., and P.S.-H. performed mammary gland processing, imaging, and transplantations, respectively. O.H., G.S.-F., M.J.S., and H.K. provided critical reagents and contributed intellectually on experimental design and interpretation of results. I.F. supervised the work and wrote the manuscript. The work was funded by AICR, BBSRC, the Royal Society, the Ludwig Institute for Cancer Research, Institut de Recherches Servier, France (to S.H. and I.F.), and Breakthrough Breast Cancer (to M.J.S.). number-of-cited-references: 36 times-cited: 23 usage-count-last-180-days: 1 usage-count-since-2013: 6 journal-iso: Dev. Cell doc-delivery-number: 005UU unique-id: ISI:000308776400012 oa: gold_or_bronze da: 2018-08-08 | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Closed research teams | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Closed research teams/Mammary Stem Cells | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Closed research teams | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Closed research teams/Mammary Stem Cells | |
pubs.volume | 23 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Mammary Stem Cells | en_US |
dc.contributor.icrauthor | Smalley, Matthew |