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 Shah, Ningling Kang

Research output: Contribution to journalArticle

34 Citations (Scopus)

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

Fingerprint

Platelet-Derived Growth Factor Receptors
Hepatic Stellate Cells
Platelet-Derived Growth Factor
Phosphorylation
Colorectal Neoplasms
Liver
Epithelial-Mesenchymal Transition
Myofibroblasts
Transforming Growth Factors
Endocytosis
Cell Movement
Neoplasms
Up-Regulation
Cell Proliferation
Cell Membrane

Keywords

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

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology (medical)
  • Physiology
  • Hepatology
  • Medicine(all)

Cite this

PDGF receptor-α promotes TGF-ß signaling in hepatic stellate cells via transcriptional and posttranscriptional regulation of TGF-ß receptors. / Liu, Chunsheng; Li, Jiachu; Xiang, Xiaoyu; Guo, Luyang; Tu, Kangsheng; Liu, Qinghua; Shah, Vijay; Kang, Ningling.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 307, No. 7, 01.10.2014, p. G749-G759.

Research output: Contribution to journalArticle

Liu, Chunsheng ; Li, Jiachu ; Xiang, Xiaoyu ; Guo, Luyang ; Tu, Kangsheng ; Liu, Qinghua ; Shah, Vijay ; Kang, Ningling. / PDGF receptor-α promotes TGF-ß signaling in hepatic stellate cells via transcriptional and posttranscriptional regulation of TGF-ß receptors. In: American Journal of Physiology - Gastrointestinal and Liver Physiology. 2014 ; Vol. 307, No. 7. pp. G749-G759.
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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.",
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T1 - PDGF receptor-α promotes TGF-ß signaling in hepatic stellate cells via transcriptional and posttranscriptional regulation of TGF-ß receptors

AU - Liu, Chunsheng

AU - Li, Jiachu

AU - Xiang, Xiaoyu

AU - Guo, Luyang

AU - Tu, Kangsheng

AU - Liu, Qinghua

AU - Shah, Vijay

AU - Kang, Ningling

PY - 2014/10/1

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N2 - 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.

AB - 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.

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KW - Myofibroblasts

KW - Receptor endocytosis and trafficking

KW - Tumor microenvironment

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