title: Caspase-mediated Cleavage of Insulin Receptor Substrate.
abstract: Apoptosis is an important mechanism for maintaining tissue homeostasis. The efficient induction and execution of apoptosis are essential for cell clearance in specific developmental situations. Insulin-like growth factor (IGF)-I is a survival factor for epithelial cells in the mammary gland, and its withdrawal or inhibition leads to apoptosis. In this paper we describe a novel mechanism that may lead to suppression of an IGF-I-mediated signaling pathway through cleavage of insulin receptor substrate (IRS). During the process of forced weaning, when mammary epithelial cells rapidly enter apoptosis in vivo, IRS-1 and IRS-2 disappear. We have used cultured mammary epithelial cells to demonstrate that IRS removal can be mediated through the action of caspase 10. Caspase 10 activation and IRS-1 cleavage are regulated by a MKK1-signaling pathway but not by a phosphatidylinositol-3 kinase pathway nor by the extracellular proapoptotic ligands FasL, tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL), or transforming growth factor-beta3. In addition we show that the loss of IRS-1 after MKK1 inhibition prevents IGF-mediated phosphorylation of FKHRL1.
authors.affiliation: School of Biological Sciences, University of Manchester, Smith Building, Oxford Road, Manchester M13 9PT, United Kingdom.
authors.forename: Kirsty A
authors.initials: KA
authors.lastname: Green
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Naylor
authors.forename: Emma T
authors.initials: ET
authors.lastname: Lowe
authors.forename: Pengbo
authors.initials: P
authors.lastname: Wang
authors.forename: Emma
authors.initials: E
authors.lastname: Marshman
authors.forename: Charles H
authors.initials: CH
authors.lastname: Streuli
mesh_terms: D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000628:therapy; D002352:Carrier Proteins / Q000378:metabolism; D053455:Caspase 10; D020169:Caspases / Q000502:physiology*; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D048369:MAP Kinase Kinase 1; D020935:MAP Kinase Signaling System; D008321:Mammary Glands, Animal / Q000201:enzymology; D051379:Mice; D008813:Mice, Inbred ICR; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D014157:Transcription Factors / Q000502:physiology; D051025:bcl-Associated Death Protein
chemical_list: C494820:Bad protein, mouse; D002352:Carrier Proteins; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; D010750:Phosphoproteins; D014157:Transcription Factors; D051025:bcl-Associated Death Protein; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; D053455:Caspase 10; D020169:Caspases