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The Prolyl Peptidases PRCP/PREP Regulate IRS-1 Stability Critical for Rapamycin-induced Feedback Activation of PI3K and AKT
- Source :
- Journal of Biological Chemistry. 289:21694-21705
- Publication Year :
- 2014
- Publisher :
- Elsevier BV, 2014.
-
Abstract
- The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT)/mammalian target of rapamycin (mTOR) pathway conveys signals from receptor tyrosine kinases (RTKs) to regulate cell metabolism, proliferation, survival, and motility. Previously we found that prolylcarboxypeptidase (PRCP) regulate proliferation and survival in breast cancer cells. In this study, we found that PRCP and the related family member prolylendopeptidase (PREP) are essential for proliferation and survival of pancreatic cancer cells. Depletion/inhibition of PRCP and PREP-induced serine phosphorylation and degradation of IRS-1, leading to inactivation of the cellular PI3K and AKT. Notably, depletion/inhibition of PRCP/PREP destabilized IRS-1 in the cells treated with rapamycin, blocking the feedback activation PI3K/AKT. Consequently, inhibition of PRCP/PREP enhanced rapamycin-induced cytotoxicity. Thus, we have identified PRCP and PREP as a stabilizer of IRS-1 which is critical for PI3K/AKT/mTOR signaling in pancreatic cancer cells.
- Subjects :
- Cell signaling
Proto-Oncogene Proteins c-akt
Carboxypeptidases
Biology
Biochemistry
Receptor tyrosine kinase
Phosphatidylinositol 3-Kinases
Enzyme activator
chemistry.chemical_compound
Cell Line, Tumor
Humans
Phosphatidylinositol
skin and connective tissue diseases
Molecular Biology
Protein kinase B
PI3K/AKT/mTOR pathway
DNA Primers
Sirolimus
Base Sequence
Serine Endopeptidases
Cell Biology
Enzyme Activation
chemistry
Insulin Receptor Substrate Proteins
Cancer research
biology.protein
Phosphorylation
Prolyl Oligopeptidases
Signal Transduction
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 289
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....80dd96ca63d04b3198f3f00778765ec9