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

The transforming growth factor-beta (TGF-beta) 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-beta 1 (LAP-TGF-beta 1). We investigated the role of NRP-1 on Smad signaling in stromal fibroblasts upon TGF-beta 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 alpha-smooth muscle actin (alpha-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-beta 1 that are mediated by distinct Smad proteins and promotes myofibroblast phenotype.