TI - ABL-1/ABI-1 Likely Act in Parallel to the CED-10 Rac and CED-1 Pathways . AB - The inhibition of engulfment by ABL-1 occurred in the absence of functional CED-2 CrkII , indicating that the effect of ABL-1 on engulfment and DTC migration is not mediated by CED-2 CrkII inhibition . In mammals , Abl PHOSphorylates tyrosine 221 of CrkII between its SH3 domains , resulting in inhibition of CrkII function and suppression of cell migration [25,68] . This tyrosine is not conserved in C.elegans . We conclude that . C.elegans ABL-1 blocks the CED-10 Rac pathway by a novel mechanism . Our analysis of genetic interactions between abl-1 and the engulfment genes suggests the existence of a new pathway involved in both cell -corpse engulfment and DTC migration . Loss of ABL-1 function suppressed the engulfment and cell -death defects of all CED-1 pathway genes tested .abl-1 mutation did not suppress the engulfment defects of ced-5 or ced-12 nulls but did suppress their DTC migration defects . Since abl-1 mutation modulated DTC migration in the absence of ced-5 or ced-12 function ( ie , when the CED-10 Rac pathway was inactive ) , ABL-1 can signal through another pathway . We propose that ABL-1 acts in a third pathway not only for DTC migration but also for engulfment . If so , this pathway cannot promote engulfment in the absence of CED-10 Rac activation . Although it is formally possible that the function of ABL-1 in engulfment is mediated through the CED-10 Rac pathway while its effect on DTC migration is mediated through a different pathway , we prefer a simpler model in which ABL-1 acts through a single pathway to oppose the engulfment genes . This pathway might act in parallel to CED-10 or it might act on CED-10 Rac ( see below ) . We found that ABI-1 is required for the function of ABL-1 in engulfment and DTC migration . ABI-1 promoted engulfment and migration independently of the known engulfment pathways downstream of or in parallel to ABL-1 . We propose that ABL-1 inhibits ABI-1 and that these two proteins define a new molecular pathway required for cell -corpse engulfment and DTC migration . Interestingly , loss of abl-1 did not suppress the engulfment defects of CED-10 Rac pathway null mutants , whereas loss of abi-1 did enhance those engulfment defects . At least three models can explain these findings . ABL-1 might not be a sufficiently potent inhibitor of ABI-1 to affect engulfment in the absence of CED-10 Rac pathway activity . Second , the CED-10 Rac pathway might be absolutely required for engulfment , so that derepressing the ABL-1/ABI-1 pathway does not suppress the CED-10 Rac pathway engulfment defect . Third , loss of abl-1 function might increase engulfment activity in the absence of the CED-10 Rac pathway insufficiently to detect in the engulfment assay . Loss of abl-1 function suppressed the DTC migration defect of a null ced-10 mutant . However , these animals were the progeny of heterozygotes and probably contained some functional CED-10 protein . Loss of abl-1 function suppressed the maternal-effect lethality of a ced-10 null mutation . This observation provides stronger evidence that abl-1 can act in parallel to or downstream of ced-10 . We were unable to test the effects of abl-1 or abi-1 mutations on a null mutant of dyn-1 , because this mutant arrests development during embryogenesis and , unlike in the case of a null ced-10 mutant , DTC migration is not affected in dyn-1 mutants . Therefore , we do not know whether ABL-1 or ABI-1 can act independently of CED-10 or DYN-1 for engulfment or engulfment-mediated programmed cell death ( or DTC migration in the case of CED-10 ) and hence whether ABL-1 and ABI-1 act through either of these genes or in a parallel molecular pathway . We think it unlikely that ABL-1 and ABI-1 act through DYN-1 , since the CED-1 pathway has no known role in DTC migration and ABL-1 and ABI-1 modulate DTC migration defects . There are atleast three models for how the ABL-1 and ABI-1 proteins act in engulfment and DTC migration . First , ABL-1 might directly inhibit ABI-1 from promoting engulfment of apoptotic cells and inappropriate DTC migration through a molecular pathway that acts in parallel to the known engulfment gene pathways ( Figure 8 ) . Second , ABI-1 might act on CED-10 Rac in parallel to the CED-5/CED-12 heterodimer ( Figure 8 ) . These models are not mutually exclusive . In a third model , the CED-10 Rac pathway and ABL-1 both act on ABI-1 in parallel to each other , with CED-10 Rac activating ABI-1 and ABL-1 inhibiting it . Studies of mammalian Abi proteins are consistent with the first two models . For example , Abi proteins are found in complexes with N-WASP [60] and the Formins [59] . Both N-WASP and formins act in actin cytoskeletal rearrangements independently of the CED-10 homolog Rac . C.elegans ABI-1 might act similarly in our first model . Abi proteins also form a complex with Eps8 and Sos-1 . Formation of the Abi-1/Eps8/Sos-1 complex activates the RacGEF activity of Sos-1 in response to tyrosine kinase signaling [50,61] . ABI-1 might act this way in our second model . In mammals , Rac and Abl proteins both act on the Scar/WAVE complex through interactions with Abi proteins [53,69] . However , in these cases Abl activates Abi . By contrast , we found that ABL-1 inhibits ABI-1 . For this reason we do not favor a model in which ABL-1 and CED-10 Rac act on ABI-1 in parallel .