VCAM-1 activates phosphatidylinositol 3-kinase and induces p120(Cbl) phosphorylation in human airway smooth muscle cells

VCAM-1 is a member of the Ig superfamily of receptors the expression of whi ch is up-regulated on human airway smooth muscle (ASM) cells following stim ulation with inflammatory mediators. The function of these receptors in adh esion is well known, but there is growing recognition that they also posses s "outside-in" signaling functions, such as cytoskeletal reorganization, ca lcium mobilization, and cytokine release. The present study examined the ac tivation of extracellular signal-regulated kinase and phosphatidylinositol 3-kinase (PUK) in ASM cells following VCAM-1 engagement, VCAM-1 ligation ac tivated extracellular signal-regulated kinase 2 and resulted in increased e xpression of cyclin D1, yet there was neither p27(kip1) degradation nor an increase in smooth muscle cell DNA synthesis. VCAM-1 ligation, however, aug mented the proliferative response to submitogenic concentrations of epiderm al growth factor, VCAM-1 engagement also stimulated a rapid increase in PI3 K activity. This was associated with phosphorylation of the adapter protein p120(Cbl) and an increase in Cbl-associated PI3K activity. These studies s uggest that VCAM-1 is linked to multiple signaling pathways in human ASM ce lls and may function to augment growth factor-induced responses.