Caspase-mediated Cleavage of Insulin Receptor Substrate.
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.
Green
Kirsty A
KA
School of Biological Sciences, University of Manchester, Smith Building, Oxford Road, Manchester M13 9PT, United Kingdom.
Naylor
Matthew J
MJ
Lowe
Emma T
ET
Wang
Pengbo
P
Marshman
Emma
E
Streuli
Charles H
CH
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
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