AGONISTIC AND ANTAGONISTIC VARIANTS OF CILIARY NEUROTROPHIC FACTOR (CNTF) REVEAL FUNCTIONAL DIFFERENCES BETWEEN MEMBRANE-BOUND AND SOLUBLE CNTF ALPHA-RECEPTOR

Ciliary neurotrophic factor (CNTF) drives the sequential assembly of a receptor complex containing the ligand-specific alpha-receptor subuni t (CNTFR) and the signal-transducing beta-subunits gp130 and leukemia inhibitory factor receptor-beta (LIFR). CNTFR can function in either m embrane-bound or soluble forms. The membrane-bound form mediates the n euronal actions of CNTF, whereas the soluble form serves to confer cyt okine responsiveness to non-neuronal cells expressing gp130 and LIFR. The objective of this work was to analyze whether the two receptor iso forms differ in their ability to interact functionally with CNTF and r elated proteins. Two new types of CNTF variants, characterized by weak ened interactions with either CNTFR or both LIFR and gp130, were devel oped, and the biological activities of these and other mutants were de termined in non-neuronal versus neuronal cells, as well as in nonneuro nal cells transfected with an expression vector for CNTFR. Membrane an choring of CNTFR was found to render the CNTF receptor complex relativ ely insensitive to changes in agonist affinity for either alpha-or bet a-receptor subunits and to promote a more efficient interaction with a gp130-depleting antagonistic variant of CNTF. As a result of this phe nomenon, which can be rationalized in terms of the multivalent nature of CNTF receptor interaction, CNTF variants display striking changes i n receptor selectivity.