LRP1 signaling in neurons and neurite-generating cell lines is determined by ligand-specific co-receptor engagement

Low density lipoprotein receptor-related protein (LRP1) functions as an endocytic receptor for a broad range of structurally and functionally diverse ligands. LRP1 also functions in cell sig-naling, directly, in response to ligand-binding, and indirectly, by regulating levels of other signaling receptors. In neurons and neurite-generating cell lines, LRP1 signaling has been reported to promote cell survival and neurite outgrowth. However, there are examples in which binding of specific ligands to LRP1 has the opposite effect. We hypothesized that ligands control the sig¬naling activity of LRP1 by directing the co-receptors that are recruited into a functional signaling complex with LRP1. We found that in PC12 and N2a cells, the NMDA receptor and Trk function with LRP1 as components of a single multi-receptor system, pro¬moting ERK activation and neurite outgrowth in response to the LRP1 ligands: tissue-type plasminogen activator (tPA) and α2-macroglobulin (α2M). Myelin-derived inhibitory proteins, such as myelin-associated glycoprotein (MAG), also bind to LRP1; however, MAG-binding does not recruit Trk or activate ERK. Instead, MAG-binding to LRP1 activates RhoA and inhibits neurite outgrowth. p75NTR, which serves as an essential co-receptor for RhoA activation by LRP1 in response to MAG, is not recruited by tPA or α2M. Although tPA and MAG both bind to the clusters of complement-like repeats (CCRs) in LRP1, the binding sites for these two ligands may not be identical. We propose a model in which LRP1 functions as a sensor for various ligands in the neuronal microenvironment, transmitting different signaling responses depending on the ligands detected. This mechanism depends on selective recruit¬ment of co-receptors. The signaling activity of LRP1, described here, may be relevant not only to its activity in neuronal survival and neurite outgrowth but also to synapse function because LRP1 is a major component of the postsynaptic density