alphavbeta5 integrin recruits the CrkII-Dock180-rac1 complex for phagocytosis of apoptotic cells.
Integrin receptors are important for the phagocytosis of apoptotic cells. However, little is known about their function in mediating internalization, as previous studies used blocking antibodies for the inhibition of binding. Here we show that the alphavbeta5 receptor mediates both binding and internalization of apoptotic cells. Internalization is dependent upon signalling through the beta5 cytoplasmic tail, and engagement of the alphavbeta5 heterodimer results in recruitment of the p130cas-CrkII-Dock180 molecular complex, which in turn triggers Rac1 activation and phagosome formation. In addition to defining integrin-receptor signalling as critical for the internalization of apoptotic material, our results also constitute the first evidence in human cells that the CED-2-CED-5-CED-10 complex defined in Caenorhabditis elegans is functionally analagous to the CrkII-Dock180-Rac1 molecular complex in mammalian cells. By linking the alphavbeta 5 receptor to this molecular switch, we reveal an evolutionarily conserved signalling pathway that is responsible for the recognition and internalization of apoptotic cells by both professional and non-professional phagocytes.
Albert
M L
ML
Laboratory of Neuro-Oncology, Rockefeller University, 1230 York Avenue, Box 226 New York 10021, USA.
Kim
J I
JI
Birge
R B
RB
D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D003713:Dendritic Cells / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D016023:Integrins / Q000235:genetics / Q000378:metabolism*; D046911:Macromolecular Substances; D010587:Phagocytosis / Q000502:physiology*; D011494:Protein Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D050737:Proto-Oncogene Proteins c-crk; D019030:Receptors, Vitronectin; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
D017931:DNA Primers; C099818:DOCK1 protein, human; D016023:Integrins; D046911:Macromolecular Substances; D011506:Proteins; D011518:Proto-Oncogene Proteins; D050737:Proto-Oncogene Proteins c-crk; D019030:Receptors, Vitronectin; D011994:Recombinant Proteins; C064660:integrin alphaVbeta5; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein