Open AccessCripto-1 Activates Nodal- and ALK4-Dependent and -Independent Signaling Pathways in Mammary Epithelial Cells
Author(s) -
Caterina Bianco,
Heather B. Adkins,
Christian Wechselberger,
Masaharu Seno,
Nicola Normanno,
Antonella De Luca,
Youping Sun,
Nazir Ahmad Khan,
Nicholas Kenney,
Andreas D. Ebert,
Kevin P. Williams,
Michele Sanicola,
David Salomon
Publication year - 2002
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.22.8.2586-2597.2002
Subject(s) - nodal signaling , biology , signal transduction , epidermal growth factor , protein kinase b , microbiology and biotechnology , phosphorylation , nodal , smad , receptor , embryo , embryogenesis , biochemistry , genetics , gastrulation
Cripto-1 (CR-1), an epidermal growth factor-CFC (EGF-CFC) family member, has a demonstrated role in embryogenesis and mammary gland development and is overexpressed in several human tumors. Recently, EGF-CFC proteins were implicated as essential signaling cofactors for Nodal, a transforming growth factor beta family member whose expression has previously been defined as embryo specific. To identify a receptor for CR-1, a human brain cDNA phage display library was screened using CR-1 protein as bait. Phage inserts with identity to ALK4, a type I serine/threonine kinase receptor for Activin, were identified. CR-1 binds to cell surface ALK4 expressed on mammalian epithelial cells in fluorescence-activated cell sorter analysis, as well as by coimmunoprecipitation. Nodal is coexpressed with mouse Cr-1 in the mammary gland, and CR-1 can phosphorylate the transcription factor Smad-2 in EpH-4 mammary epithelial cells only in the presence of Nodal and ALK4. In contrast, CR-1 stimulation of mitogen-activated protein kinase and AKT in these cells is independent of Nodal and ALK4, suggesting that CR-1 may modulate different signaling pathways to mediate its different functional roles.