PDGF receptor-α promotes TGF-ß signaling in hepatic stellate cells via transcriptional and posttranscriptional regulation of TGF-ß receptors.
Am J Physiol Gastrointest Liver Physiol
; 307(7): G749-59, 2014 Oct 01.
Article
em En
| MEDLINE
| ID: mdl-25169976
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 -ß receptors. PDGFR-α knockdown inhibits TGF-ß-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 (TßRI) but increases TßRII gene transcription. At the protein level, PDGFR-α is recruited to TßRI/TßRII complexes by TGF-ß stimulation. PDGFR-α knockdown blocks TGF-ß-mediated internalization of TßRII and induces accumulation of TßRII 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 TßRI 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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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transcrição Gênica
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Processamento de Proteína Pós-Traducional
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Fator de Crescimento Transformador beta
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Proteínas Serina-Treonina Quinases
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Receptores de Fatores de Crescimento Transformadores beta
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Receptor alfa de Fator de Crescimento Derivado de Plaquetas
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Células Estreladas do Fígado
Limite:
Animals
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Humans
Idioma:
En
Revista:
Am J Physiol Gastrointest Liver Physiol
Ano de publicação:
2014
Tipo de documento:
Article