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PMID:18432193

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Citation

Ziegenfuss, JS, Biswas, R, Avery, MA, Hong, K, Sheehan, AE, Yeung, YG, Stanley, ER and Freeman, MR (2008) Draper-dependent glial phagocytic activity is mediated by Src and Syk family kinase signalling. Nature 453:935-9

Abstract

The cellular machinery promoting phagocytosis of corpses of apoptotic cells is well conserved from worms to mammals. An important component is the Caenorhabditis elegans engulfment receptor CED-1 (ref. 1) and its Drosophila orthologue, Draper. The CED-1/Draper signalling pathway is also essential for the phagocytosis of other types of 'modified self' including necrotic cells, developmentally pruned axons and dendrites, and axons undergoing Wallerian degeneration. Here we show that Drosophila Shark, a non-receptor tyrosine kinase similar to mammalian Syk and Zap-70, binds Draper through an immunoreceptor tyrosine-based activation motif (ITAM) in the Draper intracellular domain. We show that Shark activity is essential for Draper-mediated signalling events in vivo, including the recruitment of glial membranes to severed axons and the phagocytosis of axonal debris and neuronal cell corpses by glia. We also show that the Src family kinase (SFK) Src42A can markedly increase Draper phosphorylation and is essential for glial phagocytic activity. We propose that ligand-dependent Draper receptor activation initiates the Src42A-dependent tyrosine phosphorylation of Draper, the association of Shark and the activation of the Draper pathway. These Draper-Src42A-Shark interactions are strikingly similar to mammalian immunoreceptor-SFK-Syk signalling events in mammalian myeloid and lymphoid cells. Thus, Draper seems to be an ancient immunoreceptor with an extracellular domain tuned to modified self, and an intracellular domain promoting phagocytosis through an ITAM-domain-SFK-Syk-mediated signalling cascade.

Links

PubMed PMC2493287 Online version:10.1038/nature06901

Keywords

Amino Acid Motifs; Animals; Axons/metabolism; Axons/pathology; Cell Line; Cell Membrane/metabolism; Central Nervous System; Drosophila Proteins/chemistry; Drosophila Proteins/metabolism; Intracellular Signaling Peptides and Proteins/metabolism; Membrane Proteins/chemistry; Membrane Proteins/metabolism; Neuroglia/cytology; Phagocytosis; Phosphorylation; Protein Binding; Protein Structure, Tertiary; Protein Transport; Protein-Tyrosine Kinases/metabolism; Proto-Oncogene Proteins pp60(c-src)/metabolism; Signal Transduction; Two-Hybrid System Techniques

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DROME:SHARK

involved_in

GO:0043277: apoptotic cell clearance

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:SHARK

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9W0A0

F

Seeded From UniProt

complete

DROME:SRC42

involved_in

GO:0043277: apoptotic cell clearance

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:DRPR

involved_in

GO:0043277: apoptotic cell clearance

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:DRPR

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q24145

F

Seeded From UniProt

complete


See also

References

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