Focal adhesion kinase signaling promotes phagocytosis of integrin-bound photoreceptors.
Daily alphavbeta5 integrin-dependent phagocytosis of spent photoreceptor outer segment fragments by the retinal pigment epithelium (RPE) is critical for retinal function. This study identifies a key role for focal adhesion kinase (FAK) in RPE phagocytosis. Particle binding increases FAK complex formation with alphavbeta5 receptors at the apical, phagocytic RPE surface and activates FAK. Subsequent particle engulfment coincides with dissociation of activated FAK from alphavbeta5. Mutant FAK retaining focal adhesion targeting but lacking kinase activity interferes with recruitment of full-length FAK to alphavbeta5 and abrogates FAK activation in response to RPE phagocytic challenge. Such inhibition of FAK signaling has no effect on alphavbeta5-dependent binding of particles but blocks their engulfment. Conversely, FAK re-expression promotes particle engulfment by FAK null fibroblasts. Selective ligation of alphavbeta5 receptors at the apical RPE surface is sufficient to phosphorylate and mobilize FAK. Furthermore, FAK phagocytic signaling is independent of the internalization receptor MerTK. In contrast, inhibition of FAK signaling diminishes MerTK phosphorylation. These results demonstrate that FAK provides an essential link between binding and engulfment mechanisms of integrin-mediated phagocytosis.
Finnemann
Silvia C
SC
Dyson Vision Research Institute, Department of Ophthalmology, Weill Medical College of Cornell University, New York, NY 10021, USA. sfinne@med.cornell.edu
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002460:Cell Line; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D049452:Green Fluorescent Proteins; D016023:Integrins / Q000378:metabolism*; D007700:Kinetics; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D010587:Phagocytosis; D010766:Phosphorylation; D010786:Photoreceptor Cells / Q000378:metabolism*; D010857:Pigment Epithelium of Eye / Q000166:cytology / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D051381:Rats; D020318:Rats, Long-Evans; D011922:Rats, Mutant Strains; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D019030:Receptors, Vitronectin / Q000378:metabolism*; D012374:Rod Cell Outer Segment / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D000076202:c-Mer Tyrosine Kinase
D015815:Cell Adhesion Molecules; D016023:Integrins; D008164:Luminescent Proteins; D011518:Proto-Oncogene Proteins; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5; D049452:Green Fluorescent Proteins; C490767:Mertk protein, mouse; C490765:Mertk protein, rat; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496051:Ptk2 protein, mouse; C496052:Ptk2 protein, rat