(PKCδ). Wiedmer et al. have recently reported that there are at least four homologues of the scramblase in the human and in the mouse, and it is not yet known exactly how each functions during apoptosis (12). Nearly all cells undergoing apoptosis lose phospholipid asymmetry, the only known exceptions being certain tumor cell lines (9, 13). This finding has been so reliable that phosphatidylserine is commonly used as a marker for apoptosis (eg, see ref. 14). However, it should be kept in mind that activated cells also lose phospholipid asymmetry, at least transiently. During cellular activation, the scramblase is activated, but because there is no corresponding downregulation of aminophospholipid translocase activity (15), any resulting asymmetry is soon rectified. We have shown that scramblase 1 is phosphorylated by PKCδ during cellular activation as well as during cell death, so phosphorylation per se does not appear to be the major difference between activation and death (15). Interestingly, PKCδ is cleaved during apoptosis by caspase-3, suggesting a plausible mechanism by which this kinase, and subsequently the scramblase, can become activated in a sustainable manner. When apoptosis is induced, the aminophospholipid translocase activity is downregulated, at least in part by elevation of intracellular Ca2+ levels (reviewed in ref. 8). Oxidation of phosphatidylserine during apoptosis may alter its ability to act as a substrate for transportation back to the inner leaflet by the aminophospholipid translocase (16, 17). The net result is that phosphatidylserine transport from the outer to the inner leaflet is significantly decreased. The identity of the proteins that normally mediate aminophospholipid translocase activity directionally into the inner leaflet remains somewhat controversial. Tang et al. cloned a 130-kDa P-type ATPase (ATPase type II) that can translocate phosphatidylserine in artificial membranes and that exhibits the characteristics expected of an authentic aminophospholipid translocase (18). However, when Siegmund and colleagues ablated the yeast homologue of this ATPase, they found no effect on phosphatidylserine uptake and distribution (19). Consistent with the possibility that more than one protein can serve as a phosphatidylserine translocase, Ding and colleagues have isolated four forms of ATPase II from the brain. These enzymes differ significantly with regard to ATPase activity and phospholipid selectivity, suggesting that regulation of membrane phosphatidylserine transport is complex (20). To complicate matters further, the activity of the ABC1 transporter, which helps transfer cholesterol and phospholipids from cells to protein acceptors such as apoA-I, appears to facilitate phospholipid scrambling. Deletion of the transporter gene or downregulation of its product reduces exposure of phosphatidylserine during cellular activation and apoptosis (21, 22). It has also been reported that the enhancement of apoptotic cell engulfment by phagocytes expressing ABC1 can result from loss of phospholipid asymmetry in the macrophage as well as the target cell (21, 23). Indeed, ABC1 is found in macrophages engulfing apoptotic cells during embryonic limb bud remodeling (24), and inhibition of this transporter in macrophages dramatically inhibits their uptake of apoptotic cells in vitro and in vivo. Involvement of ABC1 as a promoter of phospholipid scrambling in target cell and phagocyte is appealing, as it mimics the requirement for ced-7 function in target and phagocyte in Caenorhabditis elegans (25). How this protein works to enhance phospholipid scrambling remains a fascinating question.