Platelet-derived growth factor (PDGF) and transforming growth factor-ß(TGF-ß) 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-ß induces transdifferentiation of quiescent HSCs into myofibroblasts. Although PDGF signaling is implicated in TGF-ß-mediated epithelial mesenchymal transition of tumor cells, the role of PDGF receptors in TGF-ß activation of HSCs has not been investigated. Here we report that PDGF receptor-α (PDGFR α) is required for TGF-ß signaling of cultured human HSCs although HSCs express both PDGF α and α receptors. PDGFR α knockdown inhibits TGF- _-induced phosphorylation and nuclear accumulation of SMAD2 with no influence on AKT or ERK phosphorylation associated with noncanonical TGF-ß signaling. PDGFR α knockdown suppresses TGF-ß receptor I (T_RI) but increases T_RII gene transcription. At the protein level, PDGFR α is recruited to T_RI/T_RII complexes by TGF-ß stimulation. PDGFR α knockdown blocks TGF-ß-mediated internalization of T_RII and induces accumulation of T_RII at the plasma membrane, thereby inhibiting TGF-ß phosphorylation of SMAD2. Functionally, knockdown of PDGFR α 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 α of HSCs. In summary, our finding that PDGFR α knockdown inhibits SMAD-dependent TGF-ß signaling by repressing T_RI transcriptionally and blocking endocytosis of TGF-ß receptors highlights a convergence of PDGF and TGF-ß signaling for HSC activation and PDGFR α as a therapeutic target for liver metastasis and other settings of HSC activation.
|Original language||English (US)|
|Journal||American Journal of Physiology - Gastrointestinal and Liver Physiology|
|State||Published - Oct 1 2014|
Bibliographical notePublisher Copyright:
© 2014 the American Physiological Society.
- Colorectal liver metastasis
- Gene transcription
- Receptor endocytosis and trafficking
- Tumor microenvironment