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Blockade of Cripto binding to cell surface GRP78 inhibits oncogenic Cripto signaling via MAPK/PI3K and Smad2/3

J A Kelber1, A D Panopoulos, G Shani

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

Oncogene
|May 8, 2009
PubMed

Insights

Cell surface glucose-regulated protein-78 (GRP78) is essential for Cripto oncoprotein signaling. Blocking the Cripto/GRP78 interaction inhibits cancer cell proliferation and oncogenic pathway activation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Cripto is a developmental oncoprotein involved in embryogenesis and tumorigenesis.
  • Cripto signals through mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K)/Akt, and Smad2/3 pathways.
  • The precise molecular mechanisms of Cripto pathway coupling remain unclear.

Purpose of the Study:

  • To investigate the role of cell surface glucose-regulated protein-78 (GRP78) as a mediator of Cripto signaling.
  • To provide functional evidence for the Cripto/GRP78 complex in human tumor, mammary epithelial, and embryonic stem cells.

Main Methods:

  • Targeted disruption of the cell surface Cripto/GRP78 complex using short hairpin RNAs (shRNAs).
  • GRP78 immunoneutralization to block Cripto binding.
  • Assessment of Cripto pathway activation (MAPK/PI3K) and downstream signaling modulation (activin-A, Nodal, TGF-β1).

Main Results:

  • Cell surface GRP78 is a necessary mediator of Cripto signaling.
  • Disruption of the Cripto/GRP78 complex inhibited Cripto activation of MAPK/PI3K pathways.
  • Blockade of Cripto/GRP78 binding prevented Cripto-mediated increases in cellular proliferation, E-Cadherin downregulation, and cell adhesion.
  • Inhibition of pro-proliferative responses to activin-A and Nodal was observed.

Conclusions:

  • Cell surface GRP78 is a critical component of the Cripto signaling complex.
  • Targeting the Cripto/GRP78 binding interface effectively blocks oncogenic Cripto signaling.
  • Disrupting this interaction holds potential therapeutic value for cancer treatment.

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