OF WORK The migration of vascular smooth muscle cells (VSMCs) is a key event in the pathogenesis of many vascular diseases. We previously showed that the regulation of PDGF-directed VSMC migration by differentiation status and basic FGF (FGF-2) availability is specifically mediated through their effects on the activation of calcium/calmodulin-dependent protein kinase II (CamKII). Our current work is focussed on identifyingthe intracellular targets for CamKII, its upstream regulation, and its unique role in beta3 integrin-mediated signaling. We have shown that occupancy of beta3 integrin complexes is required for CamKII activation and VSMC migration and that signaling from beta3 integrins to CamKII occurs through a FGF2-dependent signaling pathway. In addition, we have shown that antibodies against thrombospondin (TSP) and integrin-associated protein (IAP), which is the major cell surface binding site for the C-terminal binding domain (CBD) of TSP, also block migration though the beta3 integrin- and CamKII- dependent pathways. CamKII signaling and PDGF-directed migration are also deficient in IAP-/- mice with the deficiency in migration overcome through expression of a constitutively active mutant of CamKII. These studies show that TSP, IAP, and beta3 integrins form a signaling complex that integrates extracellular signals through activation of CamKII. One of the important intracellular targets of CamKII is myosin light chain kinase (MCLK), the activity of which is suppressed by CamKII. Accordingly, pharmacological inhibition of MLCK restores PDGF-directed migration in beta3 integrin-blocked VSMCs and IAP-/- lung fibroblasts. These results identify a unique intracellular signalling network for migration in VSMCs that integrates events triggered by chemoattractant recognition and modulated by growth status, growth factors, the extracellular matrix, and ECM-VSMC interactions.
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