The prolyl peptidases PRCP/PREP regulate IRS-1 stability critical for rapamycin-induced feedback activation of PI3K and AKT.
J Biol Chem
; 289(31): 21694-705, 2014 Aug 01.
Article
in En
| MEDLINE
| ID: mdl-24936056
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Serine Endopeptidases
/
Carboxypeptidases
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Phosphatidylinositol 3-Kinases
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Sirolimus
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Proto-Oncogene Proteins c-akt
/
Insulin Receptor Substrate Proteins
Limits:
Humans
Language:
En
Journal:
J Biol Chem
Year:
2014
Document type:
Article