| First Author | Liu C | Year | 2014 |
| Journal | Am J Physiol Gastrointest Liver Physiol | Volume | 307 |
| Issue | 7 | Pages | G749-59 |
| PubMed ID | 25169976 | Mgi Jnum | J:223596 |
| Mgi Id | MGI:5659799 | Doi | 10.1152/ajpgi.00138.2014 |
| Citation | Liu C, et al. (2014) PDGF receptor-alpha promotes TGF-beta signaling in hepatic stellate cells via transcriptional and posttranscriptional regulation of TGF-beta receptors. Am J Physiol Gastrointest Liver Physiol 307(7):G749-59 |
| abstractText | Platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta) signaling are required for hepatic stellate cell (HSC) activation under pathological conditions such as liver metastatic tumor growth. These two signaling pathways are functionally divergent; PDGF signaling promotes proliferation and migration of HSCs, and TGF-beta induces transdifferentiation of quiescent HSCs into myofibroblasts. Although PDGF signaling is implicated in TGF-beta-mediated epithelial mesenchymal transition of tumor cells, the role of PDGF receptors in TGF-beta activation of HSCs has not been investigated. Here we report that PDGF receptor-alpha (PDGFR-alpha) is required for TGF-beta signaling of cultured human HSCs although HSCs express both PDGF-alpha and -beta receptors. PDGFR-alpha knockdown inhibits TGF-beta-induced phosphorylation and nuclear accumulation of SMAD2 with no influence on AKT or ERK phosphorylation associated with noncanonical TGF-beta signaling. PDGFR-alpha knockdown suppresses TGF-beta receptor I (TbetaRI) but increases TbetaRII gene transcription. At the protein level, PDGFR-alpha is recruited to TbetaRI/TbetaRII complexes by TGF-beta stimulation. PDGFR-alpha knockdown blocks TGF-beta-mediated internalization of TbetaRII and induces accumulation of TbetaRII at the plasma membrane, thereby inhibiting TGF-beta phosphorylation of SMAD2. Functionally, knockdown of PDGFR-alpha reduces paracrine effects of HSCs on colorectal cancer cell proliferation and migration in vitro. In mice and patients, colorectal cancer cell invasion of the liver induces upregulation of PDGFR-alpha of HSCs. In summary, our finding that PDGFR-alpha knockdown inhibits SMAD-dependent TGF-beta signaling by repressing TbetaRI transcriptionally and blocking endocytosis of TGF-beta receptors highlights a convergence of PDGF and TGF-beta signaling for HSC activation and PDGFR-alpha as a therapeutic target for liver metastasis and other settings of HSC activation. |
