title: New Ligand Binding Function of Human Cerberus and Role of Proteolytic Processing in Regulating Ligand-Receptor Interactions and Antagonist Activity.
abstract: Cerberus is a key regulator of vertebrate embryogenesis. Its biological function has been studied extensively in frog and mouse embryos. Its ability to bind and antagonize the transforming growth factor-β (TGF-β) family ligand Nodal is well established. Strikingly, the molecular function of Cerberus remains poorly understood. The underlying reason is that Cerberus is a complex, multifunctional protein: It binds and inhibits multiple TGF-β family ligands, it may bind and inhibit some Wnt family members, and two different forms with distinct activities have been described. In addition, sequence homology between frog and mammalian Cerberus is low, suggesting that previous studies, which analyzed frog Cerberus function, may not accurately describe the function of mammalian Cerberus. We therefore undertook to determine the molecular activities of human Cerberus in TGF-β family signaling. Using purified proteins, surface plasmon resonance, and reporter gene assays, we discovered that human Cerberus bound and inhibited the TGF-β family ligands Activin B, BMP-6, and BMP-7, but not the frog Cerberus ligand BMP-2. Notably, full-length Cerberus successfully blocked ligand binding to type II receptors, but the short form was less effective. In addition, full-length Cerberus suppressed breast cancer cell migration but the short form did not. Thus, our findings expand the roles of Cerberus as TGF-β family signaling inhibitor, provide a molecular rationale for the function of the N-terminal region, and support the idea that Cerberus could have regulatory activities beyond direct inhibition of TGF-β family signaling.
authors.affiliation: Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824-1319, USA.
authors.forename: Senem
authors.initials: S
authors.lastname: Aykul
authors.affiliation: Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824-1319, USA. Electronic address: emh@msu.edu.
authors.forename: Erik
authors.initials: E
authors.lastname: Martinez-Hackert
mesh_terms: D028341:Activins / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D016207:Cytokines / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D006801:Humans; D008969:Molecular Sequence Data; D059748:Proteolysis; D016415:Sequence Alignment; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D019485:Bone Morphogenetic Proteins; C514249:CER1 protein, human; D016207:Cytokines; D016212:Transforming Growth Factor beta; C422405:activin A; C044147:activin B; D028341:Activins
keywords: Cerberus; SPR; TGF-β; cancer; signaling