Activation of integrin alpha(v)beta(3) regulates cell adhesion and migration to bone sialoprotein

alpha(V)beta(3), a broadly distributed member of the integrin family of adh esion receptors, has been implicated in a variety of physiological and path ophysiological events, including control of bone density, angiogenesis, apo ptosis, tumor growth, and metastasis. Recently, it has been shown that acti vation of alpha(V)beta(3), its transition from a low- to a high-affinity/av idity state, in influences its recognition of certain ligands. Bone sialopr otein (BSP) is recognized as an important ligand for alpha(V)beta(3) in pro cesses ranging from bone formation to the homing of metastatic tumor cells. Here, the influence of alpha(V)beta(3) activation on the adhesion and migr ation of relevant cells to BSP has been examined. Stimulation of lymphoblas toid, osteoblastoid, and human umbilical vein endothelial cells (HUVEC) wit h PMA or Mn2+ markedly enhanced alpha(V)beta(3)-dependent adhesion to BSP. alpha(V)beta(3)-mediated migration of HUVEC or osteoblastic cells to BSP wa s substantially enhanced by stimulation, demonstrating that activation enha nces both adhesive and migratory responses. However, adhesion and/or migrat ion of certain tumor cell lines, including M21 melanoma and MDA MB435 and S KBR3 breast carcinoma cell lines, to BSP was constitutively high and was no t augmented by alpha(V)beta(3)-activating stimuli. Inhibitors of the intrac ellular signaling molecules, phosphatidylinositol 3-kinase with wortmannin, hsp90-dependent kinases with geldanamycin, and calpain with calpeptin, but not MAPKK with PD98059, reduced the high spontaneous adhesion and migratio n of the M21 cells to BSP, consistent with the constitutive activation of t he receptor on these tumor cells. These results indicate that the activatio n state of alpha(V)beta(3) can regulate cell migration and adhesion to BSP and, by extension, to other ligands of this receptor. The constitutive acti vation of alpha(V)beta(3) on neoplastic cells may contribute to tumor growt h and metastatic potential. (C) 2000 Academic Press.