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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Activin Receptors, Type I / metabolism
-
Activin Receptors, Type I / physiology*
-
Animals
-
Anti-HIV Agents
-
Antibodies, Monoclonal
-
Antibodies, Monoclonal, Humanized
-
COS Cells
-
Cell Line
-
Cell Movement / physiology
-
Cell Transformation, Neoplastic / metabolism
-
Chlorocebus aethiops
-
Enzyme Activation
-
Enzyme-Linked Immunosorbent Assay
-
Epidermal Growth Factor*
-
GPI-Linked Proteins
-
HIV Antibodies
-
Heparan Sulfate Proteoglycans / metabolism*
-
Humans
-
Intercellular Signaling Peptides and Proteins
-
Membrane Glycoproteins*
-
Mice
-
Mitogen-Activated Protein Kinases / metabolism
-
Neoplasm Proteins / antagonists & inhibitors
-
Neoplasm Proteins / metabolism*
-
Nodal Protein
-
Phosphatidylinositol Diacylglycerol-Lyase
-
Phosphorylation
-
Polysaccharide-Lyases / metabolism
-
Precipitin Tests
-
Protein Binding
-
Protein Serine-Threonine Kinases*
-
Proteins*
-
Proto-Oncogene Proteins / metabolism
-
Proto-Oncogene Proteins c-akt
-
Signal Transduction / physiology
-
Substrate Specificity
-
Transforming Growth Factor beta / metabolism
-
Transforming Growth Factor beta / physiology*
-
Type C Phospholipases / metabolism
-
src-Family Kinases / metabolism*
Substances
-
Anti-HIV Agents
-
Antibodies, Monoclonal
-
Antibodies, Monoclonal, Humanized
-
GPI-Linked Proteins
-
HIV Antibodies
-
Heparan Sulfate Proteoglycans
-
Intercellular Signaling Peptides and Proteins
-
Membrane Glycoproteins
-
NODAL protein, human
-
Neoplasm Proteins
-
Nodal Protein
-
Nodal protein, mouse
-
Proteins
-
Proto-Oncogene Proteins
-
TDGF1 protein, human
-
Tdgf1 protein, mouse
-
Transforming Growth Factor beta
-
Epidermal Growth Factor
-
src-Family Kinases
-
AKT1 protein, human
-
Protein Serine-Threonine Kinases
-
Proto-Oncogene Proteins c-akt
-
Mitogen-Activated Protein Kinases
-
ACVR1B protein, human
-
Activin Receptors, Type I
-
Acvr1b protein, mouse
-
Type C Phospholipases
-
Polysaccharide-Lyases
-
heparitinsulfate lyase
-
Phosphatidylinositol Diacylglycerol-Lyase
-
leronlimab