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

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 non-canonical TGF-beta signaling. PDGFR-alpha knockdown suppresses TGF-beta receptor I (T beta RI) but increases T beta RII gene transcription. At the protein level, PDGFR-alpha is recruited to T beta RI/T beta RII complexes by TGF-beta stimulation. PDGFR-alpha knockdown blocks TGF-beta-mediated internalization of T beta RII and induces accumulation of T beta RII 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 T beta RI 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.