Open AccessCripto Binds Transforming Growth Factor β (TGF-β) and Inhibits TGF-β Signaling
Author(s) -
Peter C. Gray,
Gidi Shani,
Kevin Aung,
Jonathan A. Kelber,
Wylie Vale
Publication year - 2006
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.01168-06
Subject(s) - biology , r smad , transforming growth factor beta , microbiology and biotechnology , transforming growth factor , tgf beta receptor 2 , signal transduction , transforming growth factor, beta 3 , tgf beta signaling pathway , cancer research , endoglin , tgf alpha , growth factor , receptor , genetics , stem cell , cd34
Cripto is a developmental oncoprotein and a member of the epidermal growth factor-Cripto, FRL-1, Cryptic family of extracellular signaling molecules. In addition to having essential functions during embryogenesis, Cripto is highly expressed in tumors and promotes tumorigenesis. During development, Cripto acts as an obligate coreceptor for transforming growth factor β (TGF-β) ligands, including nodals, growth and differentiation factor 1 (GDF1), and GDF3. As an oncogene, Cripto is thought to promote tumor growth via mechanisms including activation of mitogenic signaling pathways and antagonism of activin signaling. Here, we provide evidence supporting a novel mechanism in which Cripto inhibits the tumor suppressor function of TGF-β. Cripto bound TGF-β and reduced the association of TGF-β with its type I receptor, TβRI. Consistent with its ability to block receptor assembly, Cripto suppressed TGF-β signaling in multiple cell types and diminished the cytostatic effects of TGF-β in mammary epithelial cells. Furthermore, targeted disruption of Cripto expression by use of small inhibitory RNA enhanced TGF-β signaling, indicating that endogenous Cripto plays a role in restraining TGF-β responses.