GRP78 and Cripto Form a Complex at the Cell Surface and Collaborate To Inhibit Transforming Growth Factor β Signaling and Enhance Cell Growth

• DOI: 10.1128/mcb.01716-07
• Publication Date: 2007-11-09T01:46:25Z
• Authors: Gidi Shani; Wolfgang H. Fischer; Nicholas J. Justice; Jonathan A. Kelber; Wylie Vale; Peter C. Gray
• Keywords: 0301 basic medicine; Membrane Glycoproteins; Epidermal Growth Factor; Cell Membrane; Smad2 Protein; Cell Line; Neoplasm Proteins; 3. Good health; Mice; 03 medical and health sciences; Transforming Growth Factor beta; Animals; Humans; RNA Interference; Phosphorylation; Endoplasmic Reticulum Chaperone BiP; Receptors, Transforming Growth Factor beta; Heat-Shock Proteins; Cell Proliferation; Molecular Chaperones; Protein Binding; Signal Transduction

Cripto is a multifunctional cell surface protein with important roles in vertebrate embryogenesis and the progression of human tumors. While has been shown to modulate multiple signaling pathways, its binding partners do not appear fully explain molecular actions. Therefore, we conducted screen aimed at identifying novel Cripto-interacting proteins. This led our identification glucose-regulated 78 (GRP78), an endoplasmic reticulum (ER) chaperone that also expressed surfaces tumor cells. Here demonstrate GRP78 interact lines their interaction independent prior association within ER. Interestingly, short hairpin RNA knockdown endogenous resulted enhanced transforming growth factor β (TGF-β) signaling, indicating like Cripto, inhibits this pathway. We further show when coexpressed, collaborate antagonize TGF-β responses, including Smad phosphorylation inhibition prostate cancer cells grown under anchorage-dependent or -independent conditions. Finally, provide evidence coexpressing grow much more rapidly soft agar than expressing either individually. Together, results indicate these proteins bind enhance via signaling.