The SH2-containing inositol-5 '-phosphatase enhances LFA-1-mediated cell adhesion and defines two signaling pathways for LFA-1 activation

The inside-out signaling involved in the activation of LFA-1-mediated cell adhesion is still poorly understood, Here we examined the role of the SH2-c ontaining inositol phosphatase (SHIP), a major negative regulator of intrac ellular signaling, in this process. Wild-type SHIP and a phosphatase defici ent mutant SHIP were overexpressed in the murine myeloid cell line, DA-ER, and the effects on LFA-1-mediated cell adhesion to ICAM-1 (CD54) were teste d, Overexpression of wild-type SHIP significantly enhanced cell adhesion to immobilized ICAM-1, and PMA, IL-3, or erythropoietin further augmented thi s adhesion. In contrast, phosphatase dead SHIP had no enhancing effects. Fu rthermore, PMA-induced activation of LFA-1 on DA-ER cells overexpressing wi ldtype SHIP was dependent on protein kinase C but independent of mitogen-ac tivated protein kinase activation, whereas cytokine-induced activation was independent of protein kinase C and mitogen-activated protein kinase activa tion but required phosphatidylinositol-3 kinase activation. These results s uggest that SHIP may regulate two distinct inside-out signaling pathways an d that the phosphatase activity of SHIP is essential for both of them.