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These data demonstrate that VEGF is a novel biomarker for chronic rhinosinusitis with hyperplastic sinonasal polyposis that functions in an autocrine feed-forward manner to promote nasal epithelial cell growth and to inhibit apoptosis. These findings implicate a previously unrecognized and novel role of VEGF functioning through neuropilin-1 on nonneoplastic primary human airway epithelial cells, to amplify cell growth, contributing to exuberant hyperplastic polyposis.

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Clathrin-coated pits are now recognized to be involved in cell signaling in addition to receptor downregulation. Here we tried to identify signaling pathways that might be dependent on clathrin. Our initial data with pharmacological inhibitors of formation of clathrin-coated pits or lipid-rafts indicated that Ca 2+ response evoked by cross-linking of the high affinity receptors for IgE (FcεRI) was dependent on clathrin. To confirm this finding, we created clathrin-knockdown cells by transfecting the mast cell line RBL-2H3 with a shRNA-clathrin heavy chain construct. In these cells, the FcεRI-mediated Ca 2+ response was almost completely abolished, which was accompanied by the inhibition of sphingosine 1-phosphate (S1P) production with no changes in inositol 1,4,5-trisphosphate (IP 3 ) production. This suggests that the Ca 2+ signaling pathway via a sphingosine kinase (SK) is dependent on clathrin. Furthermore, antigen-induced tyrosine phosphorylation of p85 and p110 subunits of PI3K was almost completely inhibited in clathrin-knockdown cells. In contrast, antigen-induced tyrosine phosphorylation of phospholipase Cγ was not affected by clathrin knockdown and tyrosine phosphorylation of Syk and degranulation were partially inhibited in clathrin-knockdown cells. The present study identifies the SK/Ca 2+ pathway to be dependent on clathrin.

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