The SH2-Containing Inositol-5'-Phosphatase Enhances LFA-1-Mediated Cell Adhesion and Defines Two Signaling Pathways for LFA-1 Activation

• Published in: The Journal of immunology (1950) 1999-05, Vol.162 (10), p.5792-5799
• Main Authors: Rey-Ladino, Jose A, Huber, Michael, Liu, Ling, Damen, Jacqueline E, Krystal, Gerald, Takei, Fumio
• Format: Article
• Language: English
• Subjects: Animals; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Cell Adhesion; Erythropoietin - pharmacology; Hematopoietic Stem Cells - physiology; Intercellular Adhesion Molecule-1 - metabolism; Interleukin-3 - pharmacology; Lymphocyte Function-Associated Antigen-1 - metabolism; Mice; Phosphatidylinositol 3-Kinases - metabolism; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; Phosphoric Monoester Hydrolases - genetics; Phosphoric Monoester Hydrolases - metabolism; Protein Binding; Protein Kinase C - metabolism; Rats; Signal Transduction; src Homology Domains; Tetradecanoylphorbol Acetate - pharmacology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.162.10.5792

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-containing inositol phosphatase (SHIP), a major negative regulator of intracellular signaling, in this process. Wild-type SHIP and a phosphatase-deficient 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 tested. Overexpression of wild-type SHIP significantly enhanced cell adhesion to immobilized ICAM-1, and PMA, IL-3, or erythropoietin further augmented this adhesion. In contrast, phosphatase dead SHIP had no enhancing effects. Furthermore, PMA-induced activation of LFA-1 on DA-ER cells overexpressing wild-type SHIP was dependent on protein kinase C but independent of mitogen-activated protein kinase activation, whereas cytokine-induced activation was independent of protein kinase C and mitogen-activated protein kinase activation but required phosphatidylinositol-3 kinase activation. These results suggest that SHIP may regulate two distinct inside-out signaling pathways and that the phosphatase activity of SHIP is essential for both of them.