Gene interactions and pathways from curated databases and text-mining
Mol Cell Biol 2003, PMID: 14645548

Caveolin-1 maintains activated Akt in prostate cancer cells through scaffolding domain binding site interactions with and inhibition of serine/threonine protein phosphatases PP1 and PP2A.

Li, Likun; Ren, Cheng Hui; Tahir, Salahaldin A; Ren, Chengzhen; Thompson, Timothy C

Previously it has been reported that caveolin-1 (cav-1) has antiapoptotic activities in prostate cancer cells and functions downstream of androgenic stimulation. In this study, we demonstrate that cav-1 overexpression significantly reduced thapsigargin (Tg)-stimulated apoptosis. Examination of the phosphatidylinositol 3-kinase (PI3-K)/Akt signaling cascade revealed higher activities of PDK1 and Akt but not PI3-K in cav-1-stimulated cells compared to control cells. We subsequently found that cav-1 interacts with and inhibits serine/threonine protein phosphatases PP1 and PP2A through scaffolding domain binding site interactions. Deletion of the cav-1 scaffolding domain significantly reduces phosphorylated Akt and cell viability compared with wild-type cav-1. Analysis of potential substrates for PP1 and PP2A revealed that cav-1-mediated inhibition of PP1 and PP2A leads to increased PDK1, Akt, and ERK1/2 activities. We demonstrate that increased Akt activities are largely responsible for cav-1-mediated cell survival using dominant-negative Akt mutants and specific inhibitors to MEK1/MEK and show that cav-1 increases the half-life of phosphorylated PDK1 and Akt after inhibition of PI3-K by LY294002. We further demonstrate that cav-1-stimulated Akt activities lead to increased phosphorylation of multiple Akt substrates, including GSK3, FKHR, and MDM2. In addition, overexpression of cav-1 significantly increases translocation of phosphorylated androgen receptor to nucleus. Our studies therefore reveal a novel mechanism of Akt activation in prostate cancer and potentially other malignancies.

Diseases/Pathways annotated by Medline MESH: Prostatic Neoplasms
Document information provided by NCBI PubMed

Text Mining Data

Akt ⊣ PP2A: " Analysis of potential substrates for PP1 and PP2A revealed that cav-1 mediated inhibition of PP1 and PP2A leads to increased PDK1, Akt , and ERK1/2 activities "

Akt ⊣ PP1: " Analysis of potential substrates for PP1 and PP2A revealed that cav-1 mediated inhibition of PP1 and PP2A leads to increased PDK1, Akt , and ERK1/2 activities "

PDK1 ⊣ PP2A: " Analysis of potential substrates for PP1 and PP2A revealed that cav-1 mediated inhibition of PP1 and PP2A leads to increased PDK1 , Akt, and ERK1/2 activities "

PDK1 ⊣ PP1: " Analysis of potential substrates for PP1 and PP2A revealed that cav-1 mediated inhibition of PP1 and PP2A leads to increased PDK1 , Akt, and ERK1/2 activities "

Manually curated Databases

  • OpenBEL Selventa BEL large corpus: MAPK3 → CAV1 (increases, CAV1 Activity)
    Evidence: Modified assertion
  • OpenBEL Selventa BEL large corpus: MAPK3 → CAV1 (increases)
    Evidence: LNCaP expressing cav-1 cells treated with Thapsigargin (inducer of apoptosis) resulted in higher levels of phosphorylated PDK1and ERK1/2.
  • IRef Bind Interaction: CAV1 — PPP1CA
  • IRef Bind_translation Interaction: CAV1 — PPP1CA (unspecified method)
  • IRef Bind_translation Interaction: CAV1 — PPP1CA (imaging technique)
  • IRef Bind_translation Interaction: CAV1 — PPP1CA (coimmunoprecipitation)
  • IRef Biogrid Interaction: AKT1 — PPP1CA (direct interaction, enzymatic study)
  • IRef Biogrid Interaction: AKT1 — PPP2R4 (direct interaction, enzymatic study)
  • IRef Biogrid Interaction: PPP2R1A — CAV1 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: PPP2CA — CAV1 (direct interaction, pull down)
  • IRef Biogrid Interaction: PPP2R1B — CAV1 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: PPP2R4 — CAV1 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: AKT1 — GSK3B (direct interaction, enzymatic study)
  • IRef Biogrid Interaction: PPP1CA — CAV1 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: PPP1CA — CAV1 (direct interaction, pull down)
  • IRef Biogrid Interaction: AKT1 — GSK3A (direct interaction, enzymatic study)
In total, 9 gene pairs are associated to this article in curated databases