A Nodal- and ALK4-independent signaling pathway activated by Cripto-1 through Glypican-1 and c-Src.
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.
Bianco
Caterina
C
Mammary Biology and Tumorigenesis Laboratory, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Strizzi
Luigi
L
Rehman
Aasia
A
Normanno
Nicola
N
Wechselberger
Christian
C
Sun
Youping
Y
Khan
Nadia
N
Hirota
Morihisa
M
Adkins
Heather
H
Williams
Kevin
K
Margolis
Richard U
RU
Sanicola
Michele
M
Salomon
David S
DS
D030201:Activin Receptors, Type I / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D019380:Anti-HIV Agents; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D019556:COS Cells; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D002522:Chlorocebus aethiops; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D004815:Epidermal Growth Factor; D058851:GPI-Linked Proteins; D015483:HIV Antibodies; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D055457:Nodal Protein; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D010766:Phosphorylation; D011133:Polysaccharide-Lyases / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000502:physiology; D013379:Substrate Specificity; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000502:physiology*; D010738:Type C Phospholipases / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*
D019380:Anti-HIV Agents; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D058851:GPI-Linked Proteins; D015483:HIV Antibodies; D019812:Heparan Sulfate Proteoglycans; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C526007:NODAL protein, human; D009363:Neoplasm Proteins; D055457:Nodal Protein; C526008:Nodal protein, mouse; D011506:Proteins; D011518:Proto-Oncogene Proteins; C070636:TDGF1 protein, human; C489450:Tdgf1 protein, mouse; D016212:Transforming Growth Factor beta; D004815:Epidermal Growth Factor; D019061:src-Family Kinases; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; C498932:ACVR1B protein, human; D030201:Activin Receptors, Type I; C498933:Acvr1b protein, mouse; D010738:Type C Phospholipases; D011133:Polysaccharide-Lyases; C021349:heparitinsulfate lyase; D043265:Phosphatidylinositol Diacylglycerol-Lyase; C420063:leronlimab