A role for Mer tyrosine kinase in alphavbeta5 integrin-mediated phagocytosis of apoptotic cells.
Efficient phagocytosis of apoptotic cells is crucial for many cellular processes. One of earliest signals to the phagocyte is the expression of phosphatidylserine (PS) on the outer surface of the apoptotic cell that provides a potent 'eat-me' signal. Recognition of PS occurs either directly, via PS receptor (PS-R), or indirectly via alphavbeta5(3) integrin or Mer-family tyrosine kinases through the opsonizing proteins milk fat globule-EGF factor 8 protein (MFG-E8), or growth arrest specific factor-6 (Gas6), respectively. Because Mer and alphavbeta5 integrin share PS-dependent recognition signals, we investigated their post-receptor signaling cascades following receptor activation. Using a constitutively active form for Mer (CDMer) or Gas6 as a ligand to stimulate Mer, we found that Mer activation induced a post-receptor signaling cascade involving Src-mediated tyrosine phosphorylation of FAK on Tyr(861), the recruitment of FAK(Tyr861) to the alphavbeta5 integrin, and increased formation of p130(CAS)/CrkII/Dock180 complex to activate Rac1. Coexpression of Mer with alphavbeta5 integrin had a synergistic effect on Rac1 activation, lamellipodial formation and the phagocytosis of apoptotic cells. Interestingly, Gas6 or CDMer failed to stimulate p130(CAS) tyrosine phosphorylation or phagocytosis in beta5-deficient CS-1 cells or in mutant beta5DeltaC-expressing cells, suggesting that Mer is directionally and functionally linked to the integrin pathway. The present data indicate that receptors that recognize apoptotic cells in the context of PS functionally crosstalk to amplify intracellular signals to internalize apoptotic cells. Moreover, our data link another PS-dependent signal to the CrkII/Dock180/Rac1 module.
Wu
Yi
Y
Department of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103, USA.
Singh
Sukhwinder
S
Georgescu
Maria-Magdalena
MM
Birge
Raymond B
RB
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D050719:Crk-Associated Substrate Protein; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D016023:Integrins / Q000235:genetics / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D056484:Jumonji Domain-Containing Histone Demethylases; D051379:Mice; D008954:Models, Biological; D010587:Phagocytosis / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D050737:Proto-Oncogene Proteins c-crk; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000502:physiology; D019030:Receptors, Vitronectin / Q000235:genetics / Q000502:physiology*; D050717:Retinoblastoma-Like Protein p130; D015398:Signal Transduction / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism; D000076202:c-Mer Tyrosine Kinase; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism; D000099255:Growth Arrest-Specific Protein 6
D050719:Crk-Associated Substrate Protein; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D016023:Integrins; D036341:Intercellular Signaling Peptides and Proteins; D056484:Jumonji Domain-Containing Histone Demethylases; D011505:Protein-Tyrosine Kinases; D011506:Proteins; D011518:Proto-Oncogene Proteins; D050737:Proto-Oncogene Proteins c-crk; D020794:Receptor Protein-Tyrosine Kinases; D011956:Receptors, Cell Surface; D019030:Receptors, Vitronectin; D050717:Retinoblastoma-Like Protein p130; D014443:Tyrosine; D000076202:c-Mer Tyrosine Kinase; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D019061:src-Family Kinases; D000099255:Growth Arrest-Specific Protein 6; C493841:BCAR1 protein, human; C493842:Bcar1 protein, mouse; C099818:DOCK1 protein, human; C498708:Ptdsr protein, mouse; C107953:RAC1 protein, human; C064660:integrin alphaVbeta5; C408123:phosphatidylserine receptor; C498707:JMJD6 protein, human; C490767:Mertk protein, mouse; C496050:PTK2 protein, human; C496051:Ptk2 protein, mouse