Dab2 inhibits the cholesterol-dependent activation of JNK by TGF-beta

作者：Shapira Keren E; Hirschhorn Tal; Barzilay Lior; Smorodinsky Nechama I; Henis Yoav I^*; Ehrlich Marcelo

来源：Molecular Biology of the Cell, 2014, 25(10): 1620-1628.

DOI：10.1091/mbc.E13-09-0537

Transforming growth factor-beta (TGF-beta) ligands activate Smad-mediated and noncanonical signaling pathways in a cell context-dependent manner. Localization of signaling receptors to distinct membrane domains is a potential source of signaling output diversity. The tumor suppressor/endocytic adaptor protein disabled-2 (Dab2) was proposed as a modulator of TGF-beta signaling. However, the molecular mechanism(s) involved in the regulation of TGF-beta signaling by Dab2 were not known. Here we investigate these issues by combining biophysical studies of the lateral mobility and endocytosis of the type I TGF-beta receptor (T beta RI) with TGF-beta phosphoprotein signaling assays. Our findings demonstrate that Dab2 interacts with T beta RI to restrict its lateral diffusion at the plasma membrane and enhance its clathrinmediated endocytosis. Small interfering RNA-mediated knockdown of Dab2 or Dab2 overexpression shows that Dab2 negatively regulates TGF-beta-induced c-Jun N-terminal kinase (JNK) activation, whereas activation of the Smad pathway is unaffected. Moreover, activation of JNK by TGF-beta in the absence of Dab2 is disrupted by cholesterol depletion. These data support a model in which Dab2 regulates the domain localization of T beta RI in the membrane, balancing TGF-beta signaling via the Smad and JNK pathways.

• 出版日期2014-5-15