ArticlePloS one2012
Receptor-recognized α₂-macroglobulin binds to cell surface-associated GRP78 and activates mTORC1 and mTORC2 signaling in prostate cancer cells.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It has been retracted, and should not be counted. Cited by 28 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
28 citing papers in PubMed, 38 citations in OpenAlex.
- Article
- Retraction: Evidence for a Pro-proliferative Feedback Loop in Prostate Cancer: The role of Epac1 and COX-2-dependent Pathways.PloS one · 2025Article
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- Diversity of extracellular HSP70 in cancer: advancing from a molecular biomarker to a novel therapeutic target.Frontiers in oncology · 2024Review
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- Hepatokine Pregnancy Zone Protein Governs the Diet-Induced Thermogenesis Through Activating Brown Adipose Tissue.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2021Article
- Indomethacin Disrupts the Formation of β-Amyloid Plaques via an α2-Macroglobulin-Activating lrp1-Dependent Mechanism.International journal of molecular sciences · 2021Article
- Insulin and Metformin Control Cell Proliferation by Regulating TDG-Mediated DNA Demethylation in Liver and Breast Cancer Cells.Molecular therapy oncolytics · 2020Article
- GALNT6 promotes breast cancer metastasis by increasing mucin-type O-glycosylation of α2M.Aging · 2020Article
- Proteostasis During Cerebral Ischemia.Frontiers in neuroscience · 2019Review
- Ovostatin 2 knockdown significantly inhibits the growth, migration, and tumorigenicity of cutaneous malignant melanoma cells.PloS one · 2018Article
- ROS-independent Nrf2 activation in prostate cancer.Oncotarget · 2017Article
- Granulin-epithelin precursor interacts with 78-kDa glucose-regulated protein in hepatocellular carcinoma.BMC cancer · 2017Article
- mTOR inhibitors activate PERK signaling and favor viability of gastrointestinal neuroendocrine cell lines.Oncotarget · 2017Article
- Combination of Endothelial-Monocyte-Activating Polypeptide-II with Temozolomide Suppress Malignant Biological Behaviors of Human Glioblastoma Stem Cells via miR-590-3p/MACC1 Inhibiting PI3K/AKT/mTOR Signal Pathway.Frontiers in molecular neuroscience · 2017Article
- Activated α2-Macroglobulin Regulates Transcriptional Activation of c-MYC Target Genes through Cell Surface GRP78 Protein.The Journal of biological chemistry · 2016Article
- GRP78 and α2-macroglobulin are new promising targets for metastatic castrate-resistant prostate cancer treatment.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2015Article
- Role of GRP78 in promoting therapeutic-resistant breast cancer.Future medicinal chemistry · 2015Article
- Activated α2-macroglobulin binding to human prostate cancer cells triggers insulin-like responses.The Journal of biological chemistry · 2015Article
- Selection and identification of ligand peptides targeting a model of castrate-resistant osteogenic prostate cancer and their receptors.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
Corrections and comments
- Retraction · 2025-06-05Concerns/Issues about Image · Concerns/Issues about Results and/or Conclusions · Duplication of/in Image · Euphemisms for Duplication · Investigation by Journal/Publisher · Unreliable Data · Unreliable Results and/or Conclusions ·
- Retracted
Authors and funding
2 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
objectiveTetrameric α(2)-macroglobulin (α(2)M), a plasma panproteinase inhibitor, is activated upon interaction with a proteinase, and undergoes a major conformational change exposing a receptor recognition site in each of its subunits. Activated α(2)M (α(2)M*) binds to cancer cell surface GRP78 and triggers proliferative and antiapoptotic signaling. We have studied the role of α(2)M* in the regulation of mTORC1 and TORC2 signaling in the growth of human prostate cancer cells.
methodsEmploying immunoprecipitation techniques and Western blotting as well as kinase assays, activation of the mTORC1 and mTORC2 complexes, as well as down stream targets were studied. RNAi was also employed to silence expression of Raptor, Rictor, or GRP78 in parallel studies.
resultsStimulation of cells with α(2)M* promotes phosphorylation of mTOR, TSC2, S6-Kinase, 4EBP, Akt(T308), and Akt(S473) in a concentration and time-dependent manner. Rheb, Raptor, and Rictor also increased. α(2)M* treatment of cells elevated mTORC1 kinase activity as determined by kinase assays of mTOR or Raptor immunoprecipitates. mTORC1 activity was sensitive to LY294002 and rapamycin or transfection of cells with GRP78 dsRNA. Down regulation of Raptor expression by RNAi significantly reduced α(2)M*-induced S6-Kinase phosphorylation at T389 and kinase activity in Raptor immunoprecipitates. α(2)M*-treated cells demonstrate about a twofold increase in mTORC2 kinase activity as determined by kinase assay of Akt(S473) phosphorylation and levels of p-Akt(S473) in mTOR and Rictor immunoprecipitates. mTORC2 activity was sensitive to LY294002 and transfection of cells with GRP78 dsRNA, but insensitive to rapamycin. Down regulation of Rictor expression by RNAi significantly reduces α(2)M*-induced phosphorylation of Akt(S473) phosphorylation in Rictor immunoprecipitates.
conclusionBinding of α(2)M* to prostate cancer cell surface GRP78 upregulates mTORC1 and mTORC2 activation and promotes protein synthesis in the prostate cancer cells.
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