title: SLI-1 Cbl inhibits the engulfment of apoptotic cells in C. elegans through a ligase-independent function.
abstract: The engulfment of apoptotic cells is required for normal metazoan development and tissue remodeling. In Caenorhabditis elegans, two parallel and partially redundant conserved pathways act in cell-corpse engulfment. One pathway, which includes the small GTPase CED-10 Rac and the cytoskeletal regulator ABI-1, acts to rearrange the cytoskeleton of the engulfing cell. The CED-10 Rac pathway is also required for proper migration of the distal tip cells (DTCs) during the development of the C. elegans gonad. The second pathway includes the receptor tyrosine kinase CED-1 and might recruit membranes to extend the surface of the engulfing cell. Cbl, the mammalian homolog of the C. elegans E3 ubiquitin ligase and adaptor protein SLI-1, interacts with Rac and Abi2 and modulates the actin cytoskeleton, suggesting it might act in engulfment. Our genetic studies indicate that SLI-1 inhibits apoptotic cell engulfment and DTC migration independently of the CED-10 Rac and CED-1 pathways. We found that the RING finger domain of SLI-1 is not essential to rescue the effects of SLI-1 deletion on cell migration, suggesting that its role in this process is ubiquitin ligase-independent. We propose that SLI-1 opposes the engulfment of apoptotic cells via a previously unidentified pathway.
authors.affiliation: Yale Cancer Center and Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Courtney
authors.initials: C
authors.lastname: Anderson
authors.forename: Shan
authors.initials: S
authors.lastname: Zhou
authors.forename: Emma
authors.initials: E
authors.lastname: Sawin
authors.forename: H Robert
authors.initials: HR
authors.lastname: Horvitz
authors.forename: Michael E
authors.initials: ME
authors.lastname: Hurwitz
mesh_terms: D008841:Actin Cytoskeleton / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D017173:Caenorhabditis elegans / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D006066:Gonads / Q000254:growth & development; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D010587:Phagocytosis; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C407268:CED-10 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; C095237:Sli-1 protein, C elegans; C539886:abi-1 protein, C elegans; C422043:ced-1 protein, C elegans; D050721:Proto-Oncogene Proteins c-cbl; D020744:rac GTP-Binding Proteins