Neuropilin-1 mediates divergent R-Smad signaling and the myofibroblast phenotype.

The Journal of biological chemistry

PubMedID: 20675371

Cao Y, Szabolcs A, Dutta SK, Yaqoob U, Jagavelu K, Wang L, Leof EB, Urrutia RA, Shah VH, Mukhopadhyay D. Neuropilin-1 mediates divergent R-Smad signaling and the myofibroblast phenotype. J Biol Chem. 2010;285(41):31840-8.
The transforming growth factor-beta (TGF-ß) 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-ß1 (LAP-TGF-ß1). We investigated the role of NRP-1 on Smad signaling in stromal fibroblasts upon TGF-ß 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 a-smooth muscle actin (a-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-ß1 that are mediated by distinct Smad proteins and promotes myofibroblast phenotype.