VCAM-1 activates phosphatidylinositol 3-kinase and induces p120Cbl phosphorylation in human airway smooth muscle cells.
VCAM-1 is a member of the Ig superfamily of receptors the expression of which is up-regulated on human airway smooth muscle (ASM) cells following stimulation with inflammatory mediators. The function of these receptors in adhesion is well known, but there is growing recognition that they also possess "outside-in" signaling functions, such as cytoskeletal reorganization, calcium mobilization, and cytokine release. The present study examined the activation of extracellular signal-regulated kinase and phosphatidylinositol 3-kinase (PI3K) in ASM cells following VCAM-1 engagement. VCAM-1 ligation activated extracellular signal-regulated kinase 2 and resulted in increased expression of cyclin D1, yet there was neither p27(kip1) degradation nor an increase in smooth muscle cell DNA synthesis. VCAM-1 ligation, however, augmented the proliferative response to submitogenic concentrations of epidermal growth factor. VCAM-1 engagement also stimulated a rapid increase in PI3K activity. This was associated with phosphorylation of the adapter protein p120(Cbl) and an increase in Cbl-associated PI3K activity. These studies suggest that VCAM-1 is linked to multiple signaling pathways in human ASM cells and may function to augment growth factor-induced responses.
Lazaar
A L
AL
Pulmonary, Allergy and Critical Care Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. alazaar@mail.med.upenn.edu
Krymskaya
V P
VP
Das
S K
SK
D002455:Cell Division / Q000276:immunology; D002478:Cells, Cultured; D004357:Drug Synergism; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology; D008024:Ligands; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D009130:Muscle, Smooth / Q000166:cytology / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl; D014132:Trachea / Q000166:cytology / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism / Q000502:physiology*
D008024:Ligands; D011518:Proto-Oncogene Proteins; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D015847:Interleukin-4; D019000:Phosphotyrosine; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D019869:Phosphatidylinositol 3-Kinases; D019950:Mitogen-Activated Protein Kinase 1; C067419:CBL protein, human