Yes-associated protein (YAP65) interacts with Smad7 and potentiates its inhibitory activity against TGF-β/Smad signaling

• Published in: Oncogene Vol. 21; no. 32; pp. 4879 - 4884
• Main Authors: FERRIGNO, Olivier, LALLEMAND, Francois, VERRECCHIA, Franck, L'HOSTE, Sébastien, CAMONIS, Jacques, ATFI, Azeddine, MAUVIEL, Alain
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 25.07.2002; Nature Publishing Group; Nature Publishing Group [1987-....]
• Subjects: Activin Receptors, Type I; Activin Receptors, Type I - antagonists & inhibitors; Activin Receptors, Type I - metabolism; Adaptor Proteins, Signal Transducing; Animals; Antagonists; Biological and medical sciences; Cancer; Carrier Proteins; Carrier Proteins - metabolism; Cell Cycle Proteins; Cell physiology; Cell surface; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Clonal deletion; COS Cells; DNA-Binding Proteins; DNA-Binding Proteins - metabolism; Fundamental and applied biological sciences. Psychology; Growth factors; Intracellular; Life Sciences; Mice; Molecular and cellular biology; Phosphoproteins; Phosphoproteins - metabolism; Phosphorylation; Protein Binding; Protein-Serine-Threonine Kinases; Protein-serine/threonine kinase; Proteins; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; Receptors, Transforming Growth Factor beta - antagonists & inhibitors; Receptors, Transforming Growth Factor beta - metabolism; Signal Transduction; Smad protein; Smad3 protein; Smad7 Protein; Trans-Acti; Trans-Activators - metabolism; Transforming Growth Factor beta - metabolism; Transforming growth factor-b; Yes-associated protein; Signal transduction; Yeast; Cell line; Transforming growth factor β; Interaction; Functional analysis; Inhibition; Onc gene; Protein
• DOI: 10.1038/sj.onc.1205623
• ISSN: 0950-9232

Members of the TGF-beta family of growth factors signal from the cell surface through serine/threonine kinase receptors. Intracellular propagation of the signal occurs by phosphorylation of intracellular proteins of the Smad family. Smad7 belongs to the subclass of inhibitory Smads that function as antagonists of TGF-beta signaling. A yeast two-hybrid screen of a human placental cDNA expression library using full-length mouse Smad7 as bait identified Yes-Associated Protein (YAP65) as a novel Smad7-interacting protein. The association of Smad7 with YAP65 was confirmed using co-expressed tagged proteins in COS-7 cells. Deletion of the PY motif of Smad7 reduced but did not abolish YAP65-Smad7 association, suggesting the existence of several interacting domains. We demonstrate that YAP65 potentiates the inhibitory activity of Smad7 against TGF-beta-induced, Smad3/4-dependent, gene transactivation. Furthermore, YAP65 augments the association of Smad7 to activated TGF-beta receptor type I (TbetaRI), whereas YAP65(1-301), which exerts a dominant-negative effect against Smad7-driven inhibition of TGF-beta signaling, reduces these interactions. Together, these data provide the first evidence that YAP65 is a Smad7 partner that facilitates the recruitment of the latter to activated TbetaRI, and enhances the inhibitory activity of Smad7 against TGF-beta signaling.