Finnemann Silvia C
Dyson Vision Research Institute, Department of Ophthalmology, Weill Medical College of Cornell University, New York, NY 10021, USA.
EMBO J. 2003 Aug 15;22(16):4143-54. doi: 10.1093/emboj/cdg416.
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.
视网膜色素上皮细胞（RPE）每日对耗尽的光感受器外段片段进行的αvβ5整合素依赖性吞噬作用对视网膜功能至关重要。本研究确定了粘着斑激酶（FAK）在RPE吞噬作用中的关键作用。颗粒结合增加了FAK与位于顶端吞噬性RPE表面的αvβ5受体的复合物形成，并激活FAK。随后的颗粒吞噬与活化的FAK从αvβ5解离同时发生。保留粘着斑靶向但缺乏激酶活性的突变型FAK会干扰全长FAK向αvβ5的募集，并消除RPE吞噬挑战后FAK的激活。这种对FAK信号的抑制对颗粒的αvβ5依赖性结合没有影响，但会阻止它们的吞噬。相反，FAK的重新表达促进了FAK缺失的成纤维细胞对颗粒的吞噬。在顶端RPE表面选择性连接αvβ5受体足以使FAK磷酸化并使其动员。此外，FAK吞噬信号独立于内化受体MerTK。相比之下，抑制FAK信号会减少MerTK磷酸化。这些结果表明，FAK在整合素介导的吞噬作用的结合和吞噬机制之间提供了重要联系。
