Focal adhesion kinase signaling promotes phagocytosis of integrin-bound photoreceptors

Finnemann SC
Source: EMBO J
Publication Date: (2003)
Issue: 22(16): 4143-4154
Research Area:
Murine FAK null fibroblasts were nucleofected with either full-length FAK or GFP. Incubation of FAK expressing cells with OS increased autophosphorylation 2.5 fold. Addition of peptides containing the integrin recognition motif reduced the OS binding capacity in both FAK and GFP expressing cells, suggesting an integrin mediated mechanism to bind OS.
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.