title: Cripto-1 enhances the canonical Wnt/β-catenin signaling pathway by binding to LRP5 and LRP6 co-receptors.
abstract: Cripto-1 is implicated in multiple cellular events, including cell proliferation, motility and angiogenesis, through the activation of an intricate network of signaling pathways. A crosstalk between Cripto-1 and the canonical Wnt/β-catenin signaling pathway has been previously described. In fact, Cripto-1 is a downstream target gene of the canonical Wnt/β-catenin signaling pathway in the embryo and in colon cancer cells and T-cell factor (Tcf)/lymphoid enhancer factor binding sites have been identified in the promoter and the first intronic region of the mouse and human Cripto-1 genes. We now demonstrate that Cripto-1 modulates signaling through the canonical Wnt/β-catenin/Tcf pathway by binding to the Wnt co-receptors low-density lipoprotein receptor-related protein (LRP) 5 and LRP6, which facilitates Wnt3a binding to LRP5 and LRP6. Cripto-1 functionally enhances Wnt3a signaling through cytoplasmic stabilization of β-catenin and elevated β-catenin/Tcf transcriptional activation. Conversely, Wnt3a further increases Cripto-1 stimulation of migration, invasion and colony formation in soft agar of HC11 mouse mammary epithelial cells, indicating that Cripto-1 and the canonical Wnt/β-catenin signaling co-operate in regulating motility and in vitro transformation of mammary epithelial cells.
authors.affiliation: Tumor Growth Factor Section, Laboratory of Cancer Prevention, Frederick National Laboratory for Cancer Research, 1050 Boyles St., Bldg 560/Room 12-46, Frederick, MD 21702, USA.
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Nagaoka
authors.forename: Hideaki
authors.initials: H
authors.lastname: Karasawa
authors.forename: Thomas
authors.initials: T
authors.lastname: Turbyville
authors.forename: Maria-Cristina
authors.initials: MC
authors.lastname: Rangel
authors.forename: Nadia P
authors.initials: NP
authors.lastname: Castro
authors.forename: Monica
authors.initials: M
authors.lastname: Gonzales
authors.forename: Alyson
authors.initials: A
authors.lastname: Baker
authors.forename: Masaharu
authors.initials: M
authors.lastname: Seno
authors.forename: Stephen
authors.initials: S
authors.lastname: Lockett
authors.forename: Yoshimi E
authors.initials: YE
authors.lastname: Greer
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Rubin
authors.forename: David S
authors.initials: DS
authors.lastname: Salomon
authors.forename: Caterina
authors.initials: C
authors.lastname: Bianco
mesh_terms: D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D058851:GPI-Linked Proteins / Q000737:chemistry / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism*; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000235:genetics / Q000378:metabolism*; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009363:Neoplasm Proteins / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D015533:Transcriptional Activation; D060449:Wnt Signaling Pathway; D060509:Wnt3A Protein / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: C501127:Dkk1 protein, mouse; D058851:GPI-Linked Proteins; D036341:Intercellular Signaling Peptides and Proteins; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D009363:Neoplasm Proteins; D051899:Smad2 Protein; D051900:Smad3 Protein; C070636:TDGF1 protein, human; D060509:Wnt3A Protein; D051176:beta Catenin