Sortilin Facilitates Signaling of Ciliary Neurotrophic Factor and Related Helical Type 1 Cytokines Targeting the gp130/Leukemia Inhibitory Factor Receptor β Heterodimer

Sortilin is a member of the Vps10p domain family of neuropeptide and neurotrophin binding neuronal receptors. The family members interact with and partly share a variety of ligands and partake in intracellular sorting and protein transport as well as in transmembrane signal transduction. Thus, sortilin mediates the transport of both neurotensin and nerve growth factor and interacts with their respective receptors to facilitate ligand-induced signaling. Here we report that ciliary neurotrophic factor (CNTF), and related ligands targeting the established CNTF receptor alpha, binds to sortilin with high affinity. We find that sortilin may have at least two functions: one is to provide rapid endocytosis and the removal of CNTF, something which is not provided by CNTF receptor alpha, and the other is to facilitate CNTF signaling through the gp130/leukemia inhibitory factor (LIF) receptor beta heterodimeric complex. Interestingly, the latter function is independent of both the CNTF receptor alpha and ligand binding to sortilin but appears to implicate a direct interaction with LIF receptor beta. Thus, sortilin facilitates the signaling of all helical type 1 cytokines, which engage the gp130/LIF receptor beta complex.