Gene interactions and pathways from curated databases and text-mining
Cancer Res 2009, PMID: 19435890

RIP1 activates PI3K-Akt via a dual mechanism involving NF-kappaB-mediated inhibition of the mTOR-S6K-IRS1 negative feedback loop and down-regulation of PTEN.

Park, Seongmi; Zhao, Dawen; Hatanpaa, Kimmo J; Mickey, Bruce E; Saha, Debabrata; Boothman, David A; Story, Michael D; Wong, Eric T; Burma, Sandeep; Georgescu, Maria-Magdalena; Rangnekar, Vivek M; Chauncey, Sandili S; Habib, Amyn A

Therapeutic inhibition of mammalian target of rapamycin (mTOR) in cancer is complicated by the existence of a negative feedback loop linking mTOR to the phosphatidylinositol 3-kinase (PI3K)-Akt pathway. Thus, mTOR inhibition by rapamycin or TSC1/2 results in increased PI3K-Akt activation. The death domain kinase receptor interacting protein 1 (RIP1) plays a key role in nuclear factor-kappaB (NF-kappaB) activation and also activates the PI3K-Akt pathway through unknown mechanisms. RIP1 has recently been found to be overexpressed in glioblastoma multiforme, the most common adult primary malignant brain tumor, but not in grade II to III glioma. Our data suggest that RIP1 activates PI3K-Akt using dual mechanisms by removing the two major brakes on PI3K-Akt activity. First, increased expression of RIP1 activates PI3K-Akt by interrupting the mTOR negative feedback loop. However, unlike other signals that regulate mTOR activity without affecting its level, RIP1 negatively regulates mTOR transcription via a NF-kappaB-dependent mechanism. The second mechanism used by RIP1 to activate PI3K-Akt is down-regulation of cellular PTEN levels, which appears to be independent of NF-kappaB activation. The clinical relevance of these findings is highlighted by the demonstration that RIP1 levels correlate with activation of Akt in glioblastoma multiforme. Thus, our study shows that RIP1 regulates key components of the PTEN-PI3K-Akt-mTOR pathway and elucidates a novel negative regulation of mTOR signaling at the transcriptional level by the NF-kappaB pathway. Our data suggest that the RIP1-NF-kappaB status of tumors may influence response to treatments targeting the PTEN-PI3K-mTOR signaling axis.

Diseases/Pathways annotated by Medline MESH: Brain Neoplasms, Glioblastoma
Document information provided by NCBI PubMed

Text Mining Data

PTEN ⊣ NF-kappaB: " RIP1 activates PI3K-Akt via a dual mechanism involving NF-kappaB mediated inhibition of the mTOR-S6K-IRS1 negative feedback loop and down-regulation of PTEN "

PI3K-Akt → RIP1: " RIP1 activates PI3K-Akt via a dual mechanism involving NF-kappaB mediated inhibition of the mTOR-S6K-IRS1 negative feedback loop and down-regulation of PTEN "

PI3K-Akt → RIP1: " RIP1 activates PI3K-Akt via a dual mechanism involving NF-kappaB mediated inhibition of the mTOR-S6K-IRS1 negative feedback loop and down-regulation of PTEN "

nuclear factor-kappaB (NF-kappaB) — receptor interacting protein 1 (RIP1): " The death domain kinase receptor interacting protein 1 (RIP1) plays a key role in nuclear factor-kappaB (NF-kappaB) activation and also activates the PI3K-Akt pathway through unknown mechanisms "

PI3K-Akt → RIP1: " Our data suggest that RIP1 activates PI3K-Akt using dual mechanisms by removing the two major brakes on PI3K-Akt activity "

PI3K-Akt → RIP1: " Our data suggest that RIP1 activates PI3K-Akt using dual mechanisms by removing the two major brakes on PI3K-Akt activity "

mTOR → RIP1: " However, unlike other signals that regulate mTOR activity without affecting its level, RIP1 negatively regulates mTOR transcription via a NF-kappaB dependent mechanism "

RIP1 — NF-kappaB: " However, unlike other signals that regulate mTOR activity without affecting its level, RIP1 negatively regulates mTOR transcription via a NF-kappaB dependent mechanism "

mTOR — NF-kappaB: " However, unlike other signals that regulate mTOR activity without affecting its level, RIP1 negatively regulates mTOR transcription via a NF-kappaB dependent mechanism "

Manually curated Databases

No curated data.