The disintegrin and metalloproteinase ADAM12 contributes to TGF-beta signaling through interaction with the type II receptor

TY - JOUR

T1 - The disintegrin and metalloproteinase ADAM12 contributes to TGF-beta signaling through interaction with the type II receptor

AU - Atfi, Azeddine

AU - Dumont, Emmanuelle

AU - Colland, Frédéric

AU - Bonnier, Dominique

AU - L'helgoualc'h, Annie

AU - Prunier, Céline

AU - Ferrand, Nathalie

AU - Clément, Bruno

AU - Wewer, Ulla M.

AU - Théret, Nathalie

PY - 2007

Y1 - 2007

N2 - Transforming growth factor-beta (TGF-beta) regulates a wide variety of biological processes through two types of Ser/Thr transmembrane receptors: the TGF-beta type I receptor and the TGF-beta type II receptor (TbetaRII). Upon ligand binding, TGF-beta type I receptor activated by TbetaRII propagates signals to Smad proteins, which mediate the activation of TGF-beta target genes. In this study, we identify ADAM12 (a disintegrin and metalloproteinase 12) as a component of the TGF-beta signaling pathway that acts through association with TbetaRII. We found that ADAM12 functions by a mechanism independent of its protease activity to facilitate the activation of TGF-beta signaling, including the phosphorylation of Smad2, association of Smad2 with Smad4, and transcriptional activation. Furthermore, ADAM12 induces the accumulation of TbetaRII in early endosomal vesicles and stabilizes the TbetaRII protein presumably by suppressing the association of TbetaRII with Smad7. These results define ADAM12 as a new partner of TbetaRII that facilitates its trafficking to early endosomes in which activation of the Smad pathway is initiated.

AB - Transforming growth factor-beta (TGF-beta) regulates a wide variety of biological processes through two types of Ser/Thr transmembrane receptors: the TGF-beta type I receptor and the TGF-beta type II receptor (TbetaRII). Upon ligand binding, TGF-beta type I receptor activated by TbetaRII propagates signals to Smad proteins, which mediate the activation of TGF-beta target genes. In this study, we identify ADAM12 (a disintegrin and metalloproteinase 12) as a component of the TGF-beta signaling pathway that acts through association with TbetaRII. We found that ADAM12 functions by a mechanism independent of its protease activity to facilitate the activation of TGF-beta signaling, including the phosphorylation of Smad2, association of Smad2 with Smad4, and transcriptional activation. Furthermore, ADAM12 induces the accumulation of TbetaRII in early endosomal vesicles and stabilizes the TbetaRII protein presumably by suppressing the association of TbetaRII with Smad7. These results define ADAM12 as a new partner of TbetaRII that facilitates its trafficking to early endosomes in which activation of the Smad pathway is initiated.

KW - ADAM Proteins

KW - Animals

KW - COS Cells

KW - Cell Line

KW - Cells, Cultured

KW - Cercopithecus aethiops

KW - Fluorescent Antibody Technique

KW - Genes, Reporter

KW - Humans

KW - Luciferases

KW - Lung

KW - Membrane Proteins

KW - Mice

KW - Mink

KW - Muscle Fibers, Skeletal

KW - Plasmids

KW - Receptors, Transforming Growth Factor beta

KW - Signal Transduction

KW - Transfection

KW - Transforming Growth Factor beta

KW - Two-Hybrid System Techniques

U2 - 10.1083/jcb.200612046

DO - 10.1083/jcb.200612046

M3 - Journal article

C2 - 17620406

SN - 0021-9525

VL - 178

SP - 201

EP - 208

JO - Journal of Cell Biology

JF - Journal of Cell Biology

IS - 2

ER -