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GRP78 and Cripto form a complex at the cell surface and collaborate to inhibit transforming growth factor beta

Gidi Shani1, Wolfgang H Fischer, Nicholas J Justice

  • 1Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, La Jolla, CA, 92037, USA.

Molecular and Cellular Biology
|November 10, 2007
PubMed

Insights

Cripto and glucose-regulated protein 78 (GRP78) interact on cell surfaces, inhibiting transforming growth factor beta (TGF-beta) signaling. This collaboration enhances tumor growth, particularly in prostate cancer cells.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Protein Interactions

Background:

  • Cripto is a cell surface protein crucial for embryogenesis and tumor progression, modulating signaling pathways.
  • Existing Cripto binding partners do not fully account for its molecular functions.
  • Identification of novel Cripto-interacting proteins is necessary to elucidate its mechanisms.

Purpose of the Study:

  • To identify novel proteins that interact with Cripto.
  • To investigate the functional consequences of Cripto-GRP78 interaction.
  • To determine the role of Cripto and GRP78 in transforming growth factor beta (TGF-beta) signaling and tumor growth.

Main Methods:

  • Protein interaction screening to identify novel Cripto-binding partners.
  • Cell surface co-immunoprecipitation assays to confirm Cripto-GRP78 interaction.
  • Short hairpin RNA (shRNA) knockdown of GRP78 to assess TGF-beta signaling.
  • Analysis of Smad phosphorylation and prostate cancer cell proliferation under various conditions.
  • Soft agar assays to evaluate anchorage-independent growth.

Main Results:

  • Glucose-regulated protein 78 (GRP78), an ER chaperone, was identified as a novel Cripto-interacting protein.
  • Cripto and GRP78 interact at the cell surface, independent of ER association.
  • GRP78 knockdown enhances TGF-beta signaling, indicating GRP78's inhibitory role.
  • Coexpressed GRP78 and Cripto synergistically antagonize TGF-beta responses.
  • Prostate cancer cells coexpressing GRP78 and Cripto exhibit significantly enhanced anchorage-independent growth.

Conclusions:

  • Cripto and GRP78 form a cell surface complex that inhibits TGF-beta signaling.
  • This interaction promotes tumor growth, particularly anchorage-independent proliferation.
  • The Cripto-GRP78 complex represents a potential therapeutic target in cancer.

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