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.
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Acknowledgements
This work was supported by NCI, National Institutes of Health, Grant R01CA107420, the Foundation for Medical research, Inc., and the Robert J Jr and Helen Kleberg Foundaton. A portion of this work was also supported by an NIH training grant T32 CA009370 (to ADP) and the G Harold and Leila Y Mathers Charitable Foundation (to JCIB). Wylie W Vale is a senior investigator of the Foundation for Medical Research, Inc. and is a cofounder, consultant, equity holder and member of the Board of Directors of Neurocrine Biosciences and Acceleron Pharma. We thank Dr Travis Berggren and Margaret Lutz of The Salk Institute Stem Cell Core for valuable technical assistance.
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Kelber, J., Panopoulos, A., Shani, G. et al. Blockade of Cripto binding to cell surface GRP78 inhibits oncogenic Cripto signaling via MAPK/PI3K and Smad2/3 pathways. Oncogene 28, 2324–2336 (2009). https://doi.org/10.1038/onc.2009.97
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DOI: https://doi.org/10.1038/onc.2009.97
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