Neuropilin-1 Mediates Divergent R-Smad Signaling and the Myofibroblast Phenotype

• DOI: 10.1074/jbc.m110.151696
• Publication Date: 2010-07-31T01:09:26Z
• Authors: Ying Cao; Annamaria Szabolcs; Shamit K. Dutta; Usman Yaqoob; Kumaravelu Jagavelu; Ling Wang; Edward B. Leof; Raul A. Urrutia; Vijay H. Shah; Debabrata Mukhopa...
• Keywords: Mice, Knockout; 0303 health sciences; Fibroblasts; Smad Proteins, Receptor-Regulated; Actins; Neuropilin-1; Myoblasts; Transforming Growth Factor beta1; Mice; 03 medical and health sciences; Gene Expression Regulation; Liver; Hepatic Stellate Cells; Animals; Humans; Phosphorylation; Cell Line, Transformed; Signal Transduction

The transforming growth factor-beta (TGF-β) superfamily is one of the most diversified cell signaling pathways and regulates many physiological and pathological processes. Recently, neuropilin-1 (NRP-1) was reported to bind and activate the latent form of TGF-β1 (LAP-TGF-β1). We investigated the role of NRP-1 on Smad signaling in stromal fibroblasts upon TGF-β stimulation. Elimination of NRP-1 in stromal fibroblast cell lines increases Smad1/5 phosphorylation and downstream responses as evidenced by up-regulation of inhibitor of differentiation (Id-1). Conversely, NRP-1 loss decreases Smad2/3 phosphorylation and its responses as shown by down-regulation of α-smooth muscle actin (α-SMA) and also cells exhibit more quiescent phenotypes and growth arrest. Moreover, we also observed that NRP-1 expression is increased during the culture activation of hepatic stellate cells (HSCs), a liver resident fibroblast. Taken together, our data suggest that NRP-1 functions as a key determinant of the diverse responses downstream of TGF-β1 that are mediated by distinct Smad proteins and promotes myofibroblast phenotype.