Neuropilin-1 mediates divergent R-Smad signaling and the myofibroblast phenotype.
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.
Cao
Ying
Y
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
Szabolcs
Annamaria
A
Dutta
Shamit K
SK
Yaqoob
Usman
U
Jagavelu
Kumaravelu
K
Wang
Ling
L
Leof
Edward B
EB
Urrutia
Raul A
RA
Shah
Vijay H
VH
Mukhopadhyay
Debabrata
D
D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002461:Cell Line, Transformed; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism*; D039942:Neuropilin-1 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D051896:Smad Proteins, Receptor-Regulated / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D000199:Actins; D051896:Smad Proteins, Receptor-Regulated; D053773:Transforming Growth Factor beta1; D039942:Neuropilin-1