Lysophosphatidic acid modulates c-Met redistribution and hepatocyte growth factor/c-Met signaling in human bronchial epithelial cells through PKC δ and E-cadherin

Abstract

Previously we demonstrated that ligation of lysophosphatidic acid (LPA) to G protein-coupled LPA receptors induces transactivation of receptor tyrosine kinases (RTKs), such as platelet-derived growth factor receptor beta (PDGF-Rβ) and epidermal growth factor receptor (EGF-R), in primary cultures of human bronchial epithelial cells (HBEpCs). Here we examined the role of LPA on c-Met redistribution and modulation of hepatocyte growth factor ( These results demonstrate that LPA regulates c-Met function through PKC δ-and E-cadherin in HBEpCs, suggesting an alternate function of the cross-talk between G-protein coupled receptors (GPCRs) and RTKs in HBEpCs.

Lysophosphatidic Acid Enhances Pulmonary Epithelial Barrier Integrity and Protects Endotoxin-induced Epithelial Barrier Disruption and Lung Injury

“…The treatment of a rat neuronal cell line with LPA leads to cadherin-dependent cell adhesion following cell aggregation (52). Our previous study has shown that LPA treatment enhances airway epithelial cell clustering (45), whereas the current study suggests that LPA enhances pulmonary epithelial barrier function by inducing E-cadherin accumulation at cellcell junctions in pulmonary epithelial cells. Furthermore, posttreatment of LPA reverses the LPS-induced epithelial barrier disruption, suggesting a potential role of LPA in repairing and remodeling injured pulmonary epithelial cells after endotoxininduced acute lung injury (Fig.…”

“…We have reported that LPA induces E-cadherin/c-Met accumulation in cell-cell contacts and increases TER in HBEpCs (45). Here, for the first time, we report that LPA-induced increases in TER are dependent on PKC␦, PKC, and FAKmediated E-cadherin accumulation at cell-cell junctions.…”

“…FAK Tyr-397 is an autophosphorylation site that, when phosphorylated, recruits Src, Grb7, Shc, phospholipase ␥, and the p85 subunit of phosphoinositide 3-kinase (55). We have previously shown that LPA treatment induces accumulation of c-Met at cell-cell contacts and interacts with E-cadherin in HBEpCs and that PKC␦, but not PKC␣, regulated LPA-induced serine phosphorylation of c-Met and c-Met intracellular trafficking (45). Down-regulation of c-Met by c-Met siRNA-attenuated LPA induced the increases in TER and E-cadherin accumulation at cell-cell contacts, 3 suggesting a potential role of PKC isoforms in regulating E-cadherin intracellular trafficking via phosphorylation of c-Met and FAK in pulmonary epithelial cells.…”

“…In mouse blastocysts, upon activator treatment, PKC␦ and PKC co-relocate to cell junctions (54), suggesting that PKC␦ and PKC may play a central role in regulating cell junction membrane assembly. Our previous studies have shown that PKC␦ or PKC regulates LPA-induced signaling and biological function, including NF-B activation (31,41), epidermal growth factor receptor transactivation (38), IL-8 secretion (31), COX-2 expression (41), and c-Met accumulation at cell-cell contacts (45) in HBEpCs. Furthermore, this study demonstrates that both PKC␦ and PKC regulate the LPA-mediated E-cadherin accumulation at cell-cell junctions A, HBEpCs grown on glass chamber slides were challenged with LPS (1, 5, and 10 g/ml) for 18 h, and E-cadherin localization was detected by immunofluorescence staining with an E-cadherin antibody.…”

“…We have shown earlier that PKC␦ regulated LPA-induced c-Met intracellular trafficking from cytoplasm to plasma membrane in HBEpCs (45). Here we examined the role of specific PKC isoforms in LPA-induced increases in TER and E-cadherin accumulation at cell-cell junctions in HBEpCs.…”