1. Department of Neurobiology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, Massachusetts 01605-2324, USA
2. Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA
3. These authors contributed equally to this work.

Correspondence to: E. Richard Stanley²Marc R. Freeman¹ Correspondence and requests for materials should be addressed to M.R.F. (Email: marc.freeman@umassmed.edu) or E.R.S. (Email: rstanley@aecom.yu.edu).

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, Draper². The CED-1/Draper signalling pathway is also essential for the phagocytosis of other types of 'modified self' including necrotic cells³, developmentally pruned axons^{4, 5} and dendrites⁶, and axons undergoing Wallerian degeneration⁷. 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^{8, 9}. 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.

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