Involvement of phosphatidylinositol 3-kinase in stromal cell-derived factor-1 alpha-induced lymphocyte polarization and chemotaxis

The role of phosphatidylinositol 3-kinase (PI3-kinase), an important enzyme involved in signal transduction events, has been studied in the polarizati on and chemotaxis of lymphocytes induced by the chemokine stromal cell-deri ved factor-1 alpha (SDF-1 alpha), This chemokine was able to directly activ ate p85/p110 PI3-kinase in whole human Pal, and to induce the association o f PI3-kinase to the SDF-1 alpha receptor, CXCR4, in a pertussis toxin-sensi tive manner. Two unrelated chemical inhibitors of PI3-kinase, wortmannin an d Ly294002, prevented ICAM-3 and ERM protein moesin polarization as well as the chemotaxis of PBL in response to SDF-1 alpha. However, they did not in terfere with the reorganization of either tubulin or the actin cytoskeleton , Moreover, the transient expression of a dominant negative form of the PI3 -kinase 85-kDa regulatory subunit in the constitutively polarized Peer T ce ll line inhibited ICAM-3 polarization and markedly reduced SDF-1 alpha-indu ced chemotaxis, Conversely, overexpression of a constitutively activated mu tant of the PI3-kinase 110-kDa catalytic subunit in the round-shaped PM-1 T cell line induced ICAM-3 polarization. These results underline the role of PI3-kinase in the regulation of lymphocyte polarization and motility and i ndicate that PI3-kinase plays a selective role in the regulation of adhesio n and ERM proteins redistribution in the plasma membrane of lymphocytes.