Caspase-mediated Cleavage of Insulin Receptor Substrate
Copyright policy )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.
- University of Salford United Kingdom
Mitogen-Activated Protein Kinase Kinases, Mice, Inbred ICR, MAP Kinase Signaling System, Forkhead Box Protein O3, Intracellular Signaling Peptides and Proteins, MAP Kinase Kinase 1, Apoptosis, Breast Neoplasms, Forkhead Transcription Factors, Phosphoproteins, Mice, Mammary Glands, Animal, Caspases, Insulin Receptor Substrate Proteins, Animals, Female, Phosphorylation, Carrier Proteins, Caspase 10, Transcription Factors
Mitogen-Activated Protein Kinase Kinases, Mice, Inbred ICR, MAP Kinase Signaling System, Forkhead Box Protein O3, Intracellular Signaling Peptides and Proteins, MAP Kinase Kinase 1, Apoptosis, Breast Neoplasms, Forkhead Transcription Factors, Phosphoproteins, Mice, Mammary Glands, Animal, Caspases, Insulin Receptor Substrate Proteins, Animals, Female, Phosphorylation, Carrier Proteins, Caspase 10, Transcription Factors
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