title: Human Cerberus prevents nodal-receptor binding, inhibits nodal signaling, and suppresses nodal-mediated phenotypes.
abstract: The Transforming Growth Factor-ß (TGFß) family ligand Nodal is an essential embryonic morphogen that is associated with progression of breast and other cancers. It has therefore been suggested that Nodal inhibitors could be used to treat breast cancers where Nodal plays a defined role. As secreted antagonists, such as Cerberus, tightly regulate Nodal signaling during embryonic development, we undertook to produce human Cerberus, characterize its biochemical activities, and determine its effect on human breast cancer cells. Using quantitative methods, we investigated the mechanism of Nodal signaling, we evaluated binding of human Cerberus to Nodal and other TGFß family ligands, and we characterized the mechanism of Nodal inhibition by Cerberus. Using cancer cell assays, we examined the ability of Cerberus to suppress aggressive breast cancer cell phenotypes. We found that human Cerberus binds Nodal with high affinity and specificity, blocks binding of Nodal to its signaling partners, and inhibits Nodal signaling. Moreover, we showed that Cerberus profoundly suppresses migration, invasion, and colony forming ability of Nodal expressing and Nodal supplemented breast cancer cells. Taken together, our studies provide mechanistic insights into Nodal signaling and Nodal inhibition with Cerberus and highlight the potential value of Cerberus as anti-Nodal therapeutic.
authors.affiliation: Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan, United States of America.
authors.forename: Senem
authors.initials: S
authors.lastname: Aykul
authors.affiliation: Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan, United States of America.
authors.forename: Wendi
authors.initials: W
authors.lastname: Ni
authors.affiliation: Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan, United States of America.
authors.forename: Washington
authors.initials: W
authors.lastname: Mutatu
authors.affiliation: Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan, United States of America.
authors.forename: Erik
authors.initials: E
authors.lastname: Martinez-Hackert
mesh_terms: D030201:Activin Receptors, Type I / Q000378:metabolism; D000818:Animals; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D058851:GPI-Linked Proteins / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007700:Kinetics; D008024:Ligands; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000378:metabolism; D055457:Nodal Protein / Q000378:metabolism*; D010641:Phenotype; D011485:Protein Binding; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D058851:GPI-Linked Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D009363:Neoplasm Proteins; D055457:Nodal Protein; C070636:TDGF1 protein, human; C498932:ACVR1B protein, human; D030201:Activin Receptors, Type I; D052006:Bone Morphogenetic Protein Receptors, Type II