Gene interactions and pathways from curated databases and text-mining
Mol Cell Biol 2011, PMID: 21321085

Regulation of mTORC1 complex assembly and signaling by GRp58/ERp57.

Ramírez-Rangel, Iliana; Bracho-Valdés, Ismael; Vázquez-Macías, Aleida; Carretero-Ortega, Jorge; Reyes-Cruz, Guadalupe; Vázquez-Prado, José

The mammalian target of rapamycin (mTOR) regulates cell growth and survival via two different multiprotein complexes, mTORC1 and mTORC2. The assembly of these serine-threonine kinase multiprotein complexes occurs via poorly understood molecular mechanisms. Here, we demonstrate that GRp58/ERp57 regulates the existence and activity of mTORC1. Endogenous mTOR interacts with GRp58/ERp57 in different mammalian cells. In vitro, recombinant GRp58/ERp57 preferentially interacts with mTORC1. GRp58/ERp57 knockdown reduces mTORC1 levels and phosphorylation of 4E-BP1 and p70(S6K) in response to insulin. In contrast, GRp58/ERp57 overexpression increases mTORC1 levels and activity. A redox-sensitive mechanism that depends on GRp58/ERp57 expression activates mTORC1. Although GRp58/ERp57 is known as an endoplasmic reticulum (ER) resident, we demonstrate its presence at the cytosol, together with mTOR, Raptor, and Rictor as well as a pool of these proteins associated to the ER. In addition, the presence of GRp58/ERp57 at the ER decreases in response to insulin or leucine. Interestingly, a fraction of p70(S6K), but not 4E-BP1, is associated to the ER and phosphorylated in response to serum, insulin, or leucine. Altogether, our results suggest that GRp58/ERp57 is involved in the assembly of mTORC1 and positively regulates mTORC1 signaling at the cytosol and the cytosolic side of the ER.

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Text Mining Data

mTORC1 ⊣ insulin: " GRp58/ERp57 knockdown reduces mTORC1 levels and phosphorylation of 4E-BP1 and p70 ( S6K ) in response to insulin "

4E-BP1 ⊣ insulin: " GRp58/ERp57 knockdown reduces mTORC1 levels and phosphorylation of 4E-BP1 and p70 ( S6K ) in response to insulin "

p70 ⊣ insulin: " GRp58/ERp57 knockdown reduces mTORC1 levels and phosphorylation of 4E-BP1 and p70 ( S6K ) in response to insulin "

mTORC1 → GRp58/ERp57: " In contrast, GRp58/ERp57 overexpression increases mTORC1 levels and activity "

mTORC1 → GRp58/ERp57: " In contrast, GRp58/ERp57 overexpression increases mTORC1 levels and activity "

GRp58/ERp57 ⊣ insulin: " In addition, the presence of GRp58/ERp57 at the ER decreases in response to insulin or leucine "

Manually curated Databases

  • IRef Biogrid Interaction: RICTOR — MTOR (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: MLST8 — MTOR (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: MLST8 — RPTOR (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: PDIA3 — MTOR (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: PDIA3 — MTOR (direct interaction, two hybrid)
  • IRef Biogrid Interaction: RICTOR — PDIA3 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: PDIA3 — RPTOR (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: RPTOR — MTOR (physical association, affinity chromatography technology)
In total, 7 gene pairs are associated to this article in curated databases