Filamin associates with Smads and regulates transforming growth factor-beta signaling.
Members of the Smad proteins transmit signals triggered by the ligands of transforming growth factor (TGF)-beta superfamily. Ligand-activated receptors induce phosphorylation of so-called receptor-regulated Smads, which then accumulate in the nucleus to participate in target gene transcription, in collaboration with Smad-interacting proteins. We performed yeast two-hybrid screening and identified filamin, a cytoskeletal actin-binding protein 280, as a Smad5-interacting protein. Filamin was found to be associated not only with Smad5 but also with other Smad proteins, including TGF-beta/activin receptor-regulated Smad2. TGF-beta signaling was defective in filamin-deficient human melanoma cells M2 compared with a filamin-transfected subline A7, as determined by TGF-beta-responsive reporter gene activation and Smad2 nuclear accumulation. M2 cells restored TGF-beta responsiveness following transient transfection of full-length filamin encoding vector. The defective TGF-beta signaling in M2 cells seemed to be due to impaired receptor-induced serine phosphorylation of Smad2. These results suggest that filamin plays an important role in Smad-mediated signaling.
Department of Geriatric Research, National Institute for Longevity Sciences, Obu, Aichi 474-8522, Japan.
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A
Sasaki
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Masuda
Y
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Ohta
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Ikeda
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Watanabe
D002460:Cell Line; D003285:Contractile Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D064448:Filamins; D006801:Humans; D008840:Microfilament Proteins / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae; D015398:Signal Transduction; D051899:Smad2 Protein; D051902:Smad5 Protein; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D003285:Contractile Proteins; D004268:DNA-Binding Proteins; C578661:FLNC protein, human; D064448:Filamins; D008840:Microfilament Proteins; D010750:Phosphoproteins; C497782:SMAD2 protein, human; C497797:SMAD5 protein, human; D051899:Smad2 Protein; D051902:Smad5 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta