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PDGF receptor-? promotes TGF-? signaling in hepatic stellate cells via transcriptional and posttranscriptional regulation of TGF-? receptors.


ABSTRACT: Platelet-derived growth factor (PDGF) and transforming growth factor-? (TGF-?) 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-? induces transdifferentiation of quiescent HSCs into myofibroblasts. Although PDGF signaling is implicated in TGF-?-mediated epithelial mesenchymal transition of tumor cells, the role of PDGF receptors in TGF-? activation of HSCs has not been investigated. Here we report that PDGF receptor-? (PDGFR-?) is required for TGF-? signaling of cultured human HSCs although HSCs express both PDGF-? and -? receptors. PDGFR-? knockdown inhibits TGF-?-induced phosphorylation and nuclear accumulation of SMAD2 with no influence on AKT or ERK phosphorylation associated with noncanonical TGF-? signaling. PDGFR-? knockdown suppresses TGF-? receptor I (T?RI) but increases T?RII gene transcription. At the protein level, PDGFR-? is recruited to T?RI/T?RII complexes by TGF-? stimulation. PDGFR-? knockdown blocks TGF-?-mediated internalization of T?RII and induces accumulation of T?RII at the plasma membrane, thereby inhibiting TGF-? phosphorylation of SMAD2. Functionally, knockdown of PDGFR-? 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-? of HSCs. In summary, our finding that PDGFR-? knockdown inhibits SMAD-dependent TGF-? signaling by repressing T?RI transcriptionally and blocking endocytosis of TGF-? receptors highlights a convergence of PDGF and TGF-? signaling for HSC activation and PDGFR-? as a therapeutic target for liver metastasis and other settings of HSC activation.

PROVIDER: S-EPMC4187064 | BioStudies |

REPOSITORIES: biostudies

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