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Receptor-recognized α₂-macroglobulin binds to cell surface-associated GRP78 and activates mTORC1 and mTORC2 signaling

Uma K Misra1, Salvatore V Pizzo

  • 1Department of Pathology, Duke University Medical Center, Durham, North Carolina, United States of America.

Plos One
|December 29, 2012
PubMed
Abstract

Insights

Activated α(2)-macroglobulin (α(2)M*) binds to GRP78 on prostate cancer cells, activating mTORC1 and mTORC2 signaling pathways. This interaction promotes cell growth and protein synthesis, offering a potential therapeutic target.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Tetrameric α(2)-macroglobulin (α(2)M) is a plasma proteinase inhibitor that undergoes conformational changes upon activation.
  • Activated α(2)M (α(2)M*) binds to GRP78 on cancer cells, initiating signaling pathways that promote proliferation and inhibit apoptosis.

Purpose of the Study:

  • To investigate the role of α(2)M* in regulating mTORC1 and mTORC2 signaling pathways in human prostate cancer cell growth.
  • To elucidate the mechanism by which α(2)M* binding to GRP78 influences prostate cancer cell signaling.

Main Methods:

  • Immunoprecipitation, Western blotting, and kinase assays were used to study mTORC1 and mTORC2 complex activation and downstream targets.
  • RNA interference (RNAi) was employed to silence Raptor, Rictor, or GRP78 expression.

Main Results:

  • α(2)M* stimulation increased phosphorylation of mTOR, TSC2, S6-Kinase, 4EBP, Akt(T308), and Akt(S473) in a dose- and time-dependent manner.
  • α(2)M* treatment elevated mTORC1 and mTORC2 kinase activity, which was sensitive to specific inhibitors and GRP78 knockdown.
  • Silencing Raptor or Rictor expression via RNAi significantly reduced α(2)M*-induced signaling events.

Conclusions:

  • Binding of α(2)M* to GRP78 on prostate cancer cells upregulates both mTORC1 and mTORC2 activation.
  • This signaling cascade promotes protein synthesis, contributing to prostate cancer cell growth.

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