An Antagonist for the Leukemia Inhibitory Factor Receptor Inhibits Leukemia Inhibitory Factor, Cardiotrophin-1, Ciliary Neurotrophic Factor, and Oncostatin M

ABSTRACT 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 α, 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 α, and the other is to facilitate CNTF signaling through the gp130/leukemia inhibitory factor (LIF) receptor β heterodimeric complex. Interestingly, the latter function is independent of both the CNTF receptor α and ligand binding to sortilin but appears to implicate a direct interaction with LIF receptor β. Thus, sortilin facilitates the signaling of all helical type 1 cytokines, which engage the gp130/LIF receptor β complex.

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Identification of ciliary neurotrophic factor (CNTF) residues essential for leukemia inhibitory factor receptor binding and generation of CNTF receptor antagonists.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.93.17.9247 ◽

1996 ◽

Vol 93 (17) ◽

pp. 9247-9252 ◽

Cited By ~ 39

Author(s):

A. Di Marco ◽

I. Gloaguen ◽

R. Graziani ◽

G. Paonessa ◽

I. Saggio ◽

...

Keyword(s):

Receptor Binding ◽

Neurotrophic Factor ◽

Leukemia Inhibitory Factor ◽

Ciliary Neurotrophic Factor ◽

Inhibitory Factor ◽

Receptor Antagonists ◽

Leukemia Inhibitory Factor Receptor

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Proliferative responses and binding properties of hematopoietic cells transfected with low-affinity receptors for leukemia inhibitory factor, oncostatin M, and ciliary neurotrophic factor.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.91.3.1119 ◽

1994 ◽

Vol 91 (3) ◽

pp. 1119-1123 ◽

Cited By ~ 89

Author(s):

D. P. Gearing ◽

S. F. Ziegler ◽

M. R. Comeau ◽

D. Friend ◽

B. Thoma ◽

...

Keyword(s):

Neurotrophic Factor ◽

Leukemia Inhibitory Factor ◽

Hematopoietic Cells ◽

Ciliary Neurotrophic Factor ◽

Oncostatin M ◽

Inhibitory Factor ◽

Binding Properties

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Ciliary neurotrophic factor maintains the pluripotentiality of embryonic stem cells

Development ◽

10.1242/dev.119.3.559 ◽

1993 ◽

Vol 119 (3) ◽

pp. 559-565 ◽

Cited By ~ 6

Author(s):

J.C. Conover ◽

N.Y. Ip ◽

W.T. Poueymirou ◽

B. Bates ◽

M.P. Goldfarb ◽

...

Keyword(s):

Stem Cells ◽

Nervous System ◽

Neurotrophic Factor ◽

Leukemia Inhibitory Factor ◽

Embryonic Stem ◽

Ciliary Neurotrophic Factor ◽

Oncostatin M ◽

Inhibitory Factor ◽

Receptor Complex ◽

Ciliary Neurotrophic Factor Receptor

Ciliary neurotrophic factor was discovered based on its ability to support the survival of ciliary neurons, and is now known to act on a variety of neuronal and glial populations. Two distant relatives of ciliary neurotrophic factor, leukemia inhibitory factor and oncostatin M, mimic ciliary neurotrophic factor with respect to its actions on cells of the nervous system. In contrast to ciliary neurotrophic factor, leukemia inhibitory factor and oncostatin M also display a broad array of actions on cells outside of the nervous system. The overlapping activities of leukemia inhibitory factor, oncostatin M and ciliary neurotrophic factor can be attributed to shared receptor components. The specificity of ciliary neurotrophic factor for cells of the nervous system results from the restricted expression of the alpha component of the ciliary neurotrophic factor receptor complex, which is required to convert a functional leukemia inhibitory factor/oncostatin M receptor complex into a ciliary neurotrophic factor receptor complex. The recent observation that the alpha component of the ciliary neurotrophic factor receptor complex is expressed by very early neuronal precursors suggested that ciliary neurotrophic factor may act on even earlier precursors, particularly on cells previously thought to be targets for leukemia inhibitory factor action. Here we show the first example of ciliary neurotrophic factor responsiveness in cells residing outside of the nervous system by demonstrating that embryonic stem cells express a functional ciliary neurotrophic factor receptor complex, and that ciliary neurotrophic factor is similar to leukemia inhibitory factor in its ability to maintain the pluripotentiality of these cells.

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