Academic journal article Genetics

Signaling by the Engulfment Receptor Draper: A Screen in Drosophila Melanogaster Implicates Cytoskeletal Regulators, Jun N-Terminal Kinase, and Yorkie

Academic journal article Genetics

Signaling by the Engulfment Receptor Draper: A Screen in Drosophila Melanogaster Implicates Cytoskeletal Regulators, Jun N-Terminal Kinase, and Yorkie

Article excerpt

IN Drosophila, the transmembrane protein Draper has been shown to be required for a number of processes that involve the recognition and clearance of cellular debris. For example, Draper plays roles in the elimination of apoptotic cells by hemocytes and macrophage (Manaka et al. 2004), and is required for glial clearance of apoptotic neurons in the developing nervous system of Drosophila embryos (Freeman et al. 2003). Draper has also been shown to play a role in the engulfment of apoptotic larval axons by glia, termed axon pruning, during morphogenesis (Awasaki et al. 2006). In response to injury, severed axons are removed in a Draper dependent manner in a process termed Wallerian degeneration (MacDonald et al. 2006). Furthermore, draper (drpr) mutant flies display defects in the phagocytosis of bacteria (Cuttell et al. 2008) and Draper mediated engulfment has been linked to the process of cell competition (Li and Baker 2007), although the latter is controversial (Lolo et al. 2012). In a recent study Draper was shown to activate autophagy during cell death in Drosophila salivary glands (McPhee and Baehrecke 2010).

Genetics of engulfment of cell corpses following programmed cell death was first characterized in Caenorhabditis elegans, where two ced (cell death abnormality) pathways were identified. The drpr homolog ced-1 is part of the Ced-1, 6, 7 pathway and encodes a receptor that recognizes and engulfs dying cells (Reddien and Horvitz 2004). ced-6 encodes an adapter protein for Ced-1 signaling; ced-7 encodes a putative transporter protein that appears to play a role in both the dying and the engulfing cells (Reddien and Horvitz 2004). The second, Ced-2, 5, 10, 12 pathway was initially thought to act in parallel to mediate the cytoskeletal rearrangement required for engulfment. More recently, evidence that the Ced-1, 6, 7 pathway also feeds into Ced-10/Rac to some extent has appeared (Kinchen et al. 2005; Cabello et al. 2010). Ced-2, 5, 10 constitute an adapter complex thought to act downstream of integrins (Hsu and Wu 2010). The Drosophila homologs of ced-2, 5, and 12 are Crk, mbc (or DOCK180), and ELMO, respectively. The ced-10 homolog is Rac1. These pathways are also conserved in vertebrates (Kinchen 2010).

Many questions concerning signaling downstream of Draper remain. The adapter protein Ced-6 interacts via Draper's intracellular NPXY motif and the N-terminal phosphotyrosine binding (PTB) domain of Ced-6 (Su et al. 2002; Awasaki et al. 2006). Another protein that has been shown to mediate Draper signaling is Shark, a nonreceptor tyrosine kinase belonging to the Syk family. Shark is required for Draper function during the process of Wallerian degeneration in which axonal debris is phagocytosed by glia following injury. The interaction between Shark and Draper is mediated by an immunoreceptor tyrosine-based activation motif (ITAM) contained within the intracellular domain of Draper proteins (Ziegenfuss et al. 2008). How Shark and Ced-6 function to transduce Draper activation into the cellular process of engulfment remains incompletely known, although there appears to be a role for calcium signaling (Cuttell et al. 2008; Fullard et al. 2009). Three alternative isoforms of Draper (DrprI, DrprII, and DrprIII) have been reported (Freeman et al. 2003). The extra-cellular domain of DrprI contains 15 atypical Epidermal Growth Factor (EGF) repeats, a transmembrane domain, and an intracellular domain. The extracellular domains of DrprII and DrprIII are shorter and contain only 5 EGF motifs. The intracellular domain of DrprII contains an additional 11 amino acids (aa) compared to DrprI whereas the intracellular domain of DrprIII is truncated by a deletion of 30 aa from the C terminus. Despite these differences, the intracellular domain of each of the Draper isoforms contains a conserved NPXY motif that interacts with Ced-6. The DrprI ITAM domain that interacts with Shark is replaced by other ITAM-like sequences in DrprII, but is absent from DrprIII. …

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