A NPxY-independent β5 integrin activation signal regulates phagocytosis of apoptotic cells

Singh, Sukhwinder; D’Mello, Veera; Henegouwen, Paul van Bergen en; Birge, Raymond B.

doi:10.1016/j.bbrc.2007.10.049

Cited by 30 publications

(28 citation statements)

References 41 publications

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“…However, α V β 5 (35) and INA-1-PAT-3 (10) seem to reside at the point furthest upstream in the pathway CED-2/CED-5/CED-12/ CED-10, not CED-6/CED-7/CED-10. In addition, the NPxY motif contained in β 5 integrin was shown to be dispensable for α V β 5 -mediated phagocytosis (36). In contrast, mammalian stabilin-2, a phosphatidylserinebinding engulfment receptor, uses its NPxY motif to recruit the mammalian orthologue of CED-6 (37).…”

Section: Discussionmentioning

confidence: 99%

Role of NPxY motif in Draper-mediated apoptotic cell clearance in Drosophila

Fujita¹

2012

Drug Discov Ther

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Draper, a receptor responsible for the phagocytosis of apoptotic cells in Drosophila, possesses atypical epidermal growth factor (EGF)-like sequences in the extracellular region and the two phosphorylatable motifs NPxY and YxxL in the intracellular portion. We previously suggested that Pretaporter, a ligand for Draper, binds to the EGF-like repeat and augments the tyrosine phosphorylation of Draper. In this study, we first tested the binding of Pretaporter to various parts of the extracellular region of Draper and found that a single EGF-like sequence is sufficient for the binding. We next determined roles of the two intracellular motifs by forcedly expressing Draper proteins, in which tyrosine residues within the motifs had been substituted with phenylalanine, in hemocytes of Draper-lacking flies. We found that Draper proteins with Y-to-F substitution in either motif still underwent tyrosine phosphorylation, suggesting the occurrence of phosphorylation at both motifs. The Draper protein with substitution in the YxxL motif rescued a defect of phagocytosis, as did intact Draper, but the Draper protein with substitution in the NPxY motif did not, indicating a role of the motif NPxY, but not YxxL, in Draper-mediated phagocytosis. This coincides with our previous finding that Ced-6, an NPxYbinding signaling adaptor, is required for Draper's actions in apoptotic cell clearance. In summary, we demonstrated that Draper binds to its ligand Pretaporter using EGF-like sequences, and that the NPxY motif in the intracellular region of Draper plays an essential role in its actions as an engulfment receptor.

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Section: Discussionmentioning

confidence: 99%

Role of NPxY motif in Draper-mediated apoptotic cell clearance in Drosophila

Fujita¹

2012

Drug Discov Ther

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“…The intracellular region of ␤ subunits contains the amino acid sequence NPXY that is bound by the cytoskeleton protein talin (46), and this binding is believed essential for the activation of integrin. It is therefore worth knowing whether talin interacts with signal mediators of the engulfment pathways, although there is a report that the activation of integrin ␤ 5 in the phagocytosis of apoptotic cells occurs independent of the NPXY motif (47).…”

Section: Discussionmentioning

confidence: 99%

Integrin βν-mediated Phagocytosis of Apoptotic Cells in Drosophila Embryos

Nagaosa

Okada

Nonaka

et al. 2011

Journal of Biological Chemistry

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To identify molecules that play roles in the clearance of apoptotic cells by Drosophila phagocytes, we examined a series of monoclonal antibodies raised against larval hemocytes for effects on phagocytosis in vitro. One antibody that inhibited phagocytosis recognized terribly reduced optic lobes (Trol), a core protein of the perlecan-type proteoglycan, and the level of phagocytosis in embryos of a Trol-lacking fly line was lower than in a control line. The treatment of a hemocyte cell line with a recombinant Trol protein containing the amino acid sequence RGD augmented the phosphorylation of focal adhesion kinase, a hallmark of integrin activation. A loss of integrin ␤, one of the two ␤ subunits of Drosophila integrin, brought about a reduction in the level of apoptotic cell clearance in embryos. The presence of integrin ␤ at the surface of embryonic hemocytes was confirmed, and forced expression of integrin ␤ in hemocytes of an integrin ␤-lacking fly line recovered the defective phenotype of phagocytosis. Finally, the level of phagocytosis in a fly line that lacks both integrin ␤ and Draper, another receptor required for the phagocytosis of apoptotic cells, was lower than that in a fly line lacking either protein. We suggest that integrin ␤ serves as a phagocytosis receptor responsible for the clearance of apoptotic cells in Drosophila, independent of Draper.

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“…On the other hand, upon stimulation with Gas6, Mer triggers an anti-inflammatory pathway involving PI3K/Akt/GSK3b signaling and NF-kB inhibition in immune cells (Alciato et al, 2010;Eken et al, 2010). In addition, Mer mediates the induction of phosphorylation of cytoskeletal proteins p130cas and FAK, which have been previously implicated in apoptotic cell phagocytosis (Wu et al, 2005;Singh et al, 2007). Previously, our in vivo study found that blocking the interaction of Mer with its ligand using antiMer neutralizing antibody results in decreased LPS-induced Mer activation (given that full-length Mer protein expression is suppressed) as well as downstream signaling (Lee et al, 2012a).…”

Section: Tapi-0 Treatment Reduces Smer Production Andmentioning

confidence: 99%

Upregulation of Mer Receptor Tyrosine Kinase Signaling Attenuated Lipopolysaccharide-Induced Lung Inflammation

Choi¹,

Park²,

Lee³

et al. 2012

J Pharmacol Exp Ther

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Mer receptor tyrosine kinase (Mer) signaling plays a central role in the intrinsic inhibition of the inflammatory response to Tolllike receptor activation. Previously, we found that lung Mer protein expression decreased after lipopolysaccharide (LPS) treatment due to enhanced Mer cleavage. The purpose of the present study was to examine whether pharmacologically restored membrane-bound Mer expression upregulates the Mer signaling pathways and suppresses lung inflammatory responses. Pretreatment with the ADAM17 (a disintegrin and metalloproteinase-17) inhibitor TAPI-0 (tumor necrosis factor alpha protease inhibitor-0) reduced LPS-induced production of soluble Mer protein in bronchoalveolar lavage (BAL) fluid, restored membrane-bound Mer expression, and increased Mer activation in alveolar macrophages and lungs after LPS treatment. TAPI-0 also enhanced Mer downstream signaling, including phosphorylation of protein kinase b, focal adhesion kinase, and signal transducer and activator of transcription 1. As expected from enhanced Mer signaling, TAPI-0 also augmented suppressor of cytokine signaling-1 and -3 mRNA and protein levels and inhibited nuclear factor kB activation at 4 and 24 hours after LPS treatment. TAPI-0 suppressed LPS-induced inflammatory cell accumulation, total protein level elevation in BAL fluid, and production of inflammatory mediators, including tumor necrosis factor-a, interleukin-1b, and macrophage inflammatory protein-2. Additionally, the effects of TAPI-0 on the activation of Mer signaling and the production of inflammatory responses could be reversed by cotreatment with specific Merneutralizing antibody. Restored Mer protein expression by treatment with TAPI-0 efficiently prevents the inflammatory cascade during acute lung injury.

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A NPxY-independent β5 integrin activation signal regulates phagocytosis of apoptotic cells

Cited by 30 publications

References 41 publications

Role of NPxY motif in Draper-mediated apoptotic cell clearance in Drosophila

Role of NPxY motif in Draper-mediated apoptotic cell clearance in Drosophila

Integrin βν-mediated Phagocytosis of Apoptotic Cells in Drosophila Embryos

Upregulation of Mer Receptor Tyrosine Kinase Signaling Attenuated Lipopolysaccharide-Induced Lung Inflammation

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