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

Chunsheng Liu, Jiachu Li, Xiaoyu Xiang, Luyang Guo, Kangsheng Tu, Qinghua Liu, Vijay H. Shah, Ningling Kang

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

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 languageEnglish (US)
Pages (from-to)G749-G759
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume307
Issue number7
DOIs
StatePublished - Oct 1 2014

Keywords

  • Colorectal liver metastasis
  • Gene transcription
  • Myofibroblasts
  • Receptor endocytosis and trafficking
  • Tumor microenvironment

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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