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Transactivation of Epidermal Growth Factor Receptor Mediates Platelet‐activating Factor‐induced Proliferation of Pulmonary Vascular Smooth Muscle Cells
Author(s) -
Zhou Weilin,
Raj J Usha
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a405-a
Subject(s) - epidermal growth factor , mapk/erk pathway , epidermal growth factor receptor , transactivation , platelet derived growth factor receptor , growth factor receptor , platelet activating factor , chemistry , microbiology and biotechnology , growth factor , biology , endocrinology , kinase , medicine , signal transduction , receptor , biochemistry , transcription factor , gene
Platelet Activating Factor (PAF) mediates pulmonary vasoconstriction and also acts as a growth factor for pulmonary vascular smooth muscle cells (PVSMC) in the fetal lung. The mechanisms of PAF‐stimulated PVSMC proliferation are not fully understood. Because the PAF receptor (PAFR) is a G protein‐coupled receptor (GPCR), we hypothesized that activation of the PAFR may lead to transactivation of the epidermal growth factor receptor (EGFR) and thereby promote fetal PVSMC proliferation. Near‐term ovine fetal pulmonary vein SMC were studied in culture. We found that incubation of PVSMC with 10 nM PAF induced cell proliferation and the phosphorylation of EGFR. PAF also led to the activation of both the extracellular signal‐regulated kinase (ERK) and p38, but not the jun N‐terminal kinase mitogen‐activated protein kinase (MAPK) pathways. Specific inhibition of EGFR kinase activity by tyrphostin AG1478 and the expression of a dominant‐negative EGFR mutant in PVSMC abolished PAF‐stimulated cell proliferation. Increased alkaline phosphatase (AP) activity after 10 nM PAF treatment in AP‐tagged HB‐EGF transfected PVSMC indicated that HB‐EGF is released after PAF treatment. Inhibition of heparin‐binding EGF‐like growth factor (HB‐EGF) release by CRM197 and inhibition of matrix metalloproteinases (MMP) by GM6001 abolished PAFR‐induced p38 and ERK activation. Gelatin zymography data showed that PAF stimulated MMP‐2 activity, which could be blocked by PAFR inhibitors WEB2170 and GM6001. The results from our study suggest that PAF transactivates EGFR through MMP activation and HB‐EGF shedding from PVSMC, resulting in p38 and ERK activation and PVSMC proliferation. (Grant HL‐077819).