Trypsin stimulates the phosphorylation of p42,44 mitogen-activated protein kinases via the proteinase-activated receptor-2 and protein kinase C epsilon in human cultured prostate stromal cells |
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Authors: | Myatt Andrew Hill Stephen J |
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Affiliation: | Institute of Cell Signalling, Medical School, University of Nottingham, Nottingham, United Kingdom. mbxam1@gwmail.nottingham.ac.uk |
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Abstract: | BACKGROUND: The pathogenesis of benign prostatic hyperplasia (BPH) is not well understood. It involves the proliferation of prostate stromal cells. The proteinase-activated receptor subtype 2 (PAR-2) receptor is expressed by human prostate tissue and can be stimulated by serine proteases. Prostate epithelial cells secrete serine proteases such as trypsin, prostate specific antigen (PSA), and human glandular kallikrein (hK2). The p42,44 mitogen activated protein kinase (MAP kinase) pathway regulates cell proliferation. Trypsin can stimulate this pathway via the PAR-2 receptor and protein kinase C (PKC) in other tissues. Serine proteases secreted by prostate epithelial cells may interact with PAR-2 receptors expressed by prostate stromal cells causing them to proliferate. The aim of the present study was to establish whether functional PAR-2 receptors are expressed by human prostate stromal cells (HPSCs) and to determine whether PAR-2 stimulation can activate p42,44 MAP kinase via a pathway involving PKC. METHODS: HPSCs were cultured from patients undergoing trans urethral resection of the prostate (TURP). HPSCs were stimulated with PAR agonists. Immunoblotting of HPSC lysate with anti-p42,44 MAP kinase and -PKC isoforms. Data were analyzed with densitometry. RESULTS: Trypsin and the PAR-2 synthetic peptide SLIGKV caused significant increases in MAP kinase phosphorylation and calcium mobilization in HPSCs. The MAP kinase response was attenuated by pertussis toxin (PTX), phorbol 12,13 dibutyrate, Go6983, and Ro 318220. The PKC isoforms alpha, delta, epsilon, and zeta were detected in HPSCs. Trypsin caused the translocation of PKC(epsilon) from the cytosol to the membrane in HPSCs and was able to stimulate cellular proliferation. CONCLUSIONS: The PAR-2 selective serine protease trypsin activates p42,44 MAP kinase phosphorylation via PKC(epsilon). This may be an important mechanism of BPH pathophysiology. |
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Keywords: | benign prostatic hyperplasia stroma proteinase‐activated receptor trypsin mitogen‐activated protein kinase protein kinase C |
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