signaling the presence of cell corpses to neighboring cells that might be recognized
by CED-1. CED-7 is most similar to the subfamily ABC-1, and ABC-1 family
members have indeed been reported to promote the redistribution of
phosphatidylserins to the outer layer of the plasma membrane (Luciani and Chimini,
1996). This model is intriguing, especially since phosphatidylserins have been
supposed to play a crucial role in the recognition of dying cells (Schlegel et al., 2000;
Fadok et al., 2001; Feller, 2001; May and Machesky, 2001). ced-6, which acts
downstream of ced-1 and ced-7, encodes for an adapter protein whose primary
sequence suggests that it might interact with a tyrosine kinase pathway (Figure 6) (Liu
and Hengartner, 1998). ced-6 is functionally conserved, as human ced-6 can
complement ced-6 mutations (Liu and Hengartner, 1999). It will be interesting to
determine those signaling molecules that interact with CED-6.
ced-2, ced-5, ced-10, and ced-12 encode homologs of mammalian CrkII,
DOCK180, Rac, and ELMO, respectively (Wu and Horvitz, 1998; Reddien and
Horvitz, 2000; Gumienny et al., 2001; Wu et al., 2001b; Zhou et al., 200 1a). Recent
studies suggest that this subgroup of engulfment genes defines a conserved Rac
signaling pathway that regulates reorganization of the actin cytoskeleton of the
engulfing cell during corpse engulfment.
The small GTPase ced-10/Rac belongs, together with Rho and Cdc42, to a
subgroup of the Ras-GTPase superfamily. The Rac GTPase has been implicated in
the control of actin polymerization needed for membrane ruffling, cell motility, the
formation of lamellipodia, and phagocytosis (Tosello-Trampont et al., 2001). Genetic
studies in the worm and biochemical analysis in mammalian cells suggest that CED-2/
Crk, CED-5/DOCK180, and CED-12/ELMO function as upstream activators of
CED-10/Rac (Figure 6) (Gumienny et al., 2001; Wu et al., 2001b). Human CrkII
is a cytoskeleton-associated adapter protein consisting of a SH2 (Srchomology-2)
domain followed by two C-terminal SH3 (Src-homology-3) domains, and it has been
implicated in integrin-mediated signaling and cell movement (Matsuda et al., 1991).
CrkII localizes to focal adhesions with p130CAS and DOCK180, which was isolated
on the basis of its physical interaction with the first SH3 domain of CrkII (Hasegawa
et al., 1996; Erickson et al., 1997). CED-12 shares homology with members of the
gene family ELMO, defined by three human orthologs, ELMO1, 2, and 3, and one
ortholog in Drosophila (Gumienny et al., 2001; Zhou et al., 2001a). Both DOCK180
and ELMO1, under the control of a C. elegans heat-shock promoter, can rescue the
migration defect of the DTC, but not the engulfment defect in ced-5-mutant animals.
Detailed interaction analysis suggests an evolutionarily conserved trimeric complex
between CED–12/ELMO, CED-5/DOCK180, and CED-2/CrkII (Figure 6)
(Gumienny et al., 2001). How does this putative ELMO/DOCK180/CrkII complex
activate the Rac GTPase? Ras-related GTP-binding proteins function as molecular
switches that cycle between GTP-bound ‘on’ and GDP-bound ‘off states regulating
downstream effector molecules. Exchange of the bound GDP is facilitated by
guanidine-nucleotide-exchange factors (GEFs). Several experiments have been done
to determine the possible Rac-GEF activity of the ELMO: DOCK180: CrkII
complex. However, it is unlikely that the ELMO: DOCK180: CrkII complex acts
180 GENETICS OF APOPTOSIS