Antibody cross-linking of the glycosylphosphatidylinositol-linked protein CD59 on hematopoietic cells induces signaling pathways resembling activation by complement.
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.
Murray
E W
EW
Cancer Biology and Immunology Research Groups, Departments of Oncology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Robbins
S M
SM
D000906:Antibodies / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000378:metabolism*; D018957:CD59 Antigens / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D010641:Phenotype; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
D000906:Antibodies; D018957:CD59 Antigens; D011518:Proto-Oncogene Proteins; D014443:Tyrosine; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D011505:Protein-Tyrosine Kinases; C067419:CBL protein, human