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1 Department of Molecular Biomedical Sciences, North Carolina State University, Collge of Veterinary Medicine, Raleigh, NC, USA
* To whom correspondence should be addressed. E-mail: philip_sannes{at}ncsu.edu.
Undersulfation of the basement membrane (BM) matrix of alveolar type II (AT2) cells compared with that of neighboring type I cells is believed to account for some of the known morphologic and functional differences between these pneumocytes. Heparin, a model for sulfated components of BM matrices, is known to inhibit fibroblast growth factor-2 (FGF-2)-stimulated DNA synthesis as well as gene expression of FGF-2 and its receptor in AT2 cells. To determine if these end points result from specific effects of heparin on FGF-related signaling pathways, isolated rat AT2 cells were treated with 100 ng/ml FGF-1 or FGF-2 in the presence of up to 500 µg/ml heparin. In addition, experiments were done on cells grown in the presence of 20 mM sodium chlorate (sulfation inhibitor). High-dose heparin reduced FGF-1- or FGF-2-stimulated phosphorylation of mitogen-activated protein kinase kinases (MEK1/2), p44/42 mitogen-activated protein kinases (MAPK/Erk1/2), stress activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), Akt/Protein Kinase B (Akt/PKB), and p90RSK. FGF-2-stimulated signaling was more sensitive to heparin's effects than was signaling stimulated by FGF-1. Heparin had an additive effect on the reduced [3H]thymidine incorporation in FGF-2-treated AT2 cells caused by inhibition of the MEK-Erk pathway by the MEK-inhibitor PD98059. The data suggest that heparin's known capacity to alter DNA synthesis and possibly other biological end points is realized via cross talk between multiple signaling pathways.
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