Paradoxical Roles of Leucine-Rich α-Glycoprotein-1 in Cell Death and Survival Modulated by Transforming Growth Factor-Beta 1 and Cytochrome .

Leucine-rich α-glycoprotein-1 (LRG1) has been shown to impact both apoptosis and cell survival, pleiotropic effects similar to one of its known ligands, transforming growth factor-beta 1 (TGF-β1). Recent studies have given insight into the TGF-β1 signaling pathways involved in LRG1-mediated death versus survival signaling, i.e., canonical or non-canonical. Interaction of LRG1 with another ligand, extracellular cytochrome (Cyt ), promotes cell survival, at least for lymphocytes. LRG1 has been shown to bind Cyt with high affinity, higher than it binds TGF-β1, making it sensitive to small changes in the level of extracellular Cyt within a microenvironment that may arise from cell death. Evidence is presented here that LRG1 can bind TGF-β1 and Cyt simultaneously, raising the possibility that the ternary complex may present a signaling module with the net effect of signaling, cell death versus survival, determined by the relative extent to which the LRG1 binding sites are occupied by these two ligands. A possible role for LRG1 should be considered in studies where extracellular effects of TGF-β1 and Cyt have been observed in media supplemented with LRG1-containing serum.