| Abstrakt: |
The αvβ3integrin has been shown to bind several ligands, including osteopontin and vitronectin. Its role in modulating cell migration and downstream signaling pathways in response to specific extracellular matrix ligands has been investigated in this study. Highly invasive prostate cancer PC3 cells that constitutively express αvβ3adhere and migrate on osteopontin and vitronectin in an αvβ3-dependent manner. However, exogenous expression of αvβ3in noninvasive prostate cancer LNCaP (β3-LNCaP) cells mediates adhesion and migration on vitronectin but not on osteopontin. Activation of αvβ3by epidermal growth factor stimulation is required to mediate adhesion to osteopontin but is not sufficient to support migration on this substrate. We show that αvβ3-mediated cell migration requires activation of the phosphatidylinositol 3-kinase (PI 3-kinase)/protein kinase B (PKB/AKT) pathway since wortmannin, a PI 3-kinase inhibitor, prevents PC3 cell migration on both osteopontin and vitronectin; furthermore, αvβ3engagement by osteopontin and vitronectin activates the PI 3-kinase/AKT pathway. Migration of β3-LNCaP cells on vitronectin also occurs through activation of the PI 3-kinase pathway; however, AKT phosphorylation is not increased upon engagement by osteopontin. Furthermore, phosphorylation of focal adhesion kinase (FAK), known to support cell migration in β3-LNCaP cells, is detected on both substrates. Thus, in PC3 cells, αvβ3mediates cell migration and PI 3-kinase/AKT pathway activation on vitronectin and osteopontin; in β3-LNCaP cells, αvβ3mediates cell migration and PI 3-kinase/AKT pathway activation on vitronectin, whereas adhesion to osteopontin does not support αvβ3-mediated cell migration and PI 3-kinase/AKT pathway activation. We conclude therefore that αvβ3exists in multiple functional states that can bind either selectively vitronectin or both vitronectin and osteopontin and that can differentially activate cell migration and intracellular signaling pathways in a ligand-specific manner. |
