Abl Kinase Inhibits the Engulfment of Apopotic Cells in Caenorhabditis elegans

Open Access
Publisher Website
Google Scholar
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 includes the adaptor protein CED-2 CrkII and the small GTPase CED-10 Rac, and acts to rearrange the cytoskeleton of the engulfing cell. The other pathway includes the receptor tyrosine kinase CED-1 and might recruit membranes to extend the surface of the engulfing cell. Although many components required for engulfment have been identified, little is known about inhibition of engulfment. The tyrosine kinase Abl regulates the actin cytoskeleton in mammals and Drosophila in multiple ways. For example, Abl inhibits cell migration via phosphorylation of CrkII. We tested whether ABL-1, the C. elegans ortholog of Abl, inhibits the CED-2 CrkII-dependent engulfment of apoptotic cells. Our genetic studies indicate that ABL-1 inhibits apoptotic cell engulfment, but not through CED-2 CrkII, and instead acts in parallel to the two known engulfment pathways. 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 loss of ABL-1 function partially restores normal DTC migration in the CED-10 Rac pathway mutants. We found that ABI-1 the C. elegans homolog of mammalian Abi (Abl interactor) proteins, is required for engulfment of apoptotic cells and proper DTC migration. Like Abl, Abi proteins are cytoskeletal regulators. ABI-1 acts in parallel to the two known engulfment pathways, likely downstream of ABL-1. ABL-1 and ABI-1 interact physically in vitro. We propose that ABL-1 opposes the engulfment of apoptotic cells by inhibiting ABI-1 via a pathway that is distinct from the two known engulfment pathways. Cell death or apoptosis is a normal part of animal development, as is the engulfment and removal of dead cells by other cells. In the nematode Caenorhabditis elegans, ten highly conserved proteins have been characterized previously for their roles in engulfment and in cell migration, both of which involve the formation of cellular extensions. Little is known, however, about how engulfment is inhibited. In mammals, the tyrosine kinase Abl, which regulates the actin cytoskeleton and which when misexpressed causes two types of leukemia, prevents the CrkII protein from facilitating cell migration. CrkII functions in engulfment in C. elegans and mammals. We tested whether the C. elegans homolog of Abl, ABL-1, could inhibit engulfment. We found that ABL-1 functions as an inhibitor of apoptotic cell engulfment and cell migration. However, our analysis further showed that ABL-1 does not function by inhibiting other known engulfment proteins, including C. elegans CrkII. Our data indicate that ABL-1 blocks ABI-1, the C. elegans homolog of the mammalian and Drosophila Abl-interactor (Abi) cytoskeletal-regulatory proteins. We propose that ABL-1 acts via ABI-1 to inhibit a newly identified pathway during cell corpse engulfment and cell migration.