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

J. A. Kelber, A. D. Panopoulos, G. Shani, E. C. Booker, Juan Carlos Izpisua Belmonte, W. W. Vale, P. C. Gray

Research output: Contribution to journalArticlepeer-review

134 Scopus citations

Abstract

Cripto is a developmental oncoprotein that signals via mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K)/Akt and Smad2/3 pathways. However, the molecular basis for Cripto coupling to these pathways during embryogenesis and tumorigenesis is not fully understood. In this regard, we recently demonstrated that Cripto forms a cell surface complex with the HSP70 family member glucose-regulated protein-78 (GRP78). Here, we provide novel functional evidence demonstrating that cell surface GRP78 is a necessary mediator of Cripto signaling in human tumor, mammary epithelial and embryonic stem cells. We show that targeted disruption of the cell surface Cripto/GRP78 complex using shRNAs or GRP78 immunoneutralization precludes Cripto activation of MAPK/PI3K pathways and modulation of activin-A, activin-B, Nodal and transforming growth factor-Β1 signaling. We further demonstrate that blockade of Cripto binding to cell surface GRP78 prevents Cripto from increasing cellular proliferation, downregulating E-Cadherin, decreasing cell adhesion and promoting pro-proliferative responses to activin-A and Nodal. Thus, disrupting the Cripto/GRP78 binding interface blocks oncogenic Cripto signaling and may have important therapeutic value in the treatment of cancer.

Original languageEnglish (US)
Pages (from-to)2324-2336
Number of pages13
JournalOncogene
Volume28
Issue number24
DOIs
StatePublished - Jun 18 2009

Keywords

  • Akt
  • Cancer
  • Cripto
  • GRP78
  • MAPK
  • Stem cell
  • TGF-β

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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