CD59 is a
glycosylphosphatidylinositol-anchored
cell surface glycoprotein involved in protecting cells from host-mediated
complement attack. Studies have shown that antibody cross-linking of CD59 induces a series of intracellular signaling events including the activation of
protein-tyrosine kinases (PTK). To further characterize these events,
antibodies and
complement 8, one of the natural
ligands of CD59, were used to activate CD59. Antibody-induced cross-linking of CD59 on the surface of THP-1 and U937 hematopoietic cell lines as well as exposure to
complement 8 induces a rapid increase in the
tyrosine phosphorylation of several
proteins within the cell. Consistent with an early role for the Src family PTKs in these signaling events, we found that transient activation of Hck- and CD59-mediated signaling was abrogated in the presence of the Src family PTK-selective inhibitor PP1. Although the molecular mechanism by which CD59 communicates to Hck is unknown, cellular fractionation studies indicated that both CD59 and Hck are compartmentalized in plasma membrane microdomains. We also detected
tyrosine phosphorylation of the adaptor
proteins p120 and Shc, and the cytoplasmic nonreceptor
tyrosine kinase Syk. The identification of CD59-mediated signaling events may help explain why
paroxysmal nocturnal hemoglobinuria patients, who are deficient in
glycosylphosphatidylinositol-linked proteins including CD59, are susceptible to proliferative disorders.