A Nodal- and ALK4-independent signaling pathway activated by Cripto-1 through Glypican-1 and c-Src.
basic_science · Level V
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Abstract
Human Cripto-1 (CR-1) is a member of the epidermal growth factor-Cripto FRL1 Cryptic family that has been shown to function as a coreceptor with the type I Activin serine-threonine kinase receptor ALK4 for the transforming growth factor beta-related peptide Nodal. However, CR-1 can also activate the mitogen-activated protein kinase and Akt pathways independently of Nodal and ALK4 by an unknown mechanism. Here, we demonstrate that CR-1 specifically binds to Glypican-1, a membrane-associated heparan sulfate proteoglycan, and activates the tyrosine kinase c-Src, triggering the mitogen-activated protein kinase and Akt signaling pathways. Finally, an active Src kinase is necessary for CR-1 to induce in vitro transformation and migration in mouse mammary epithelial cells.
Medical subject headings
- Activin Receptors, Type I
- Epidermal Growth Factor
- Heparan Sulfate Proteoglycans
- Membrane Glycoproteins
- Neoplasm Proteins
- Protein Serine-Threonine Kinases
- Proteins
- Transforming Growth Factor beta
- src-Family Kinases