The α(v)β3 integrin 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 invasire prostate cancer PC3 cells that constitutively express α(v)β3 adhere and migrate on osteopontin and vitronectin in an α(v)β3-dependent manner. However, exogenous expression of α(v)β3 in noninvasive prostate cancer LNCaP (β3-LNCaP) cells mediates adhesion and migration on vitronectin but not on osteopontin. Activation of α(v)β3 by epidermal growth factor stimulation is required to mediate adhesion to osteopontin but is not sufficient to support migration on this substrate. We show that α(v)β3-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, α(v)β3 engagement 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, α(v)β3 mediates cell migration and PI 3-kinase/AKT pathway activation on vitronectin and osteopontin; in β3-LNCaP cells, α(v)β3 mediates cell migration and PI 3-kinase/AKT pathway activation on vitronectin, whereas adhesion to osteopontin does not support α(v)β3-mediated cell migration and PI 3-kinase/AKT pathway activation. We conclude therefore that α(v)β3 exists 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.
Zheng, D.-Q., Woodard, A.S., Tallini, G., Languino, L.R. (2000). Substrate specificity of α(v)β3 integrin-mediated cell migration and phosphatidylinositol 3-kinase/AKT pathway activation. THE JOURNAL OF BIOLOGICAL CHEMISTRY, 275(32), 24565-24574 [10.1074/jbc.M002646200].
Substrate specificity of α(v)β3 integrin-mediated cell migration and phosphatidylinositol 3-kinase/AKT pathway activation
Tallini G.;
2000
Abstract
The α(v)β3 integrin 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 invasire prostate cancer PC3 cells that constitutively express α(v)β3 adhere and migrate on osteopontin and vitronectin in an α(v)β3-dependent manner. However, exogenous expression of α(v)β3 in noninvasive prostate cancer LNCaP (β3-LNCaP) cells mediates adhesion and migration on vitronectin but not on osteopontin. Activation of α(v)β3 by epidermal growth factor stimulation is required to mediate adhesion to osteopontin but is not sufficient to support migration on this substrate. We show that α(v)β3-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, α(v)β3 engagement 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, α(v)β3 mediates cell migration and PI 3-kinase/AKT pathway activation on vitronectin and osteopontin; in β3-LNCaP cells, α(v)β3 mediates cell migration and PI 3-kinase/AKT pathway activation on vitronectin, whereas adhesion to osteopontin does not support α(v)β3-mediated cell migration and PI 3-kinase/AKT pathway activation. We conclude therefore that α(v)β3 exists 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
