scholarly journals Engineering a potent receptor superagonist or antagonist from a novel IL-6 family cytokine ligand

2020 ◽  
Vol 117 (25) ◽  
pp. 14110-14118
Author(s):  
Jun W. Kim ◽  
Cesar P. Marquez ◽  
R. Andres Parra Sperberg ◽  
Jiaxiang Wu ◽  
Won G. Bae ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Leukemia Inhibitory Factor ◽  
Nonsmall Cell Lung Cancer ◽  
Ciliary Neurotrophic Factor ◽  
Leukemia Inhibitory Factor Receptor ◽  
Receptor Complexes ◽  
Signaling Axis ◽  
Xenograft Models ◽  
Family Cytokine ◽  
Ciliary Neurotrophic Factor Receptor

Interleukin-6 (IL-6) family cytokines signal through multimeric receptor complexes, providing unique opportunities to create novel ligand-based therapeutics. The cardiotrophin-like cytokine factor 1 (CLCF1) ligand has been shown to play a role in cancer, osteoporosis, and atherosclerosis. Once bound to ciliary neurotrophic factor receptor (CNTFR), CLCF1 mediates interactions to coreceptors glycoprotein 130 (gp130) and leukemia inhibitory factor receptor (LIFR). By increasing CNTFR-mediated binding to these coreceptors we generated a receptor superagonist which surpassed the potency of natural CNTFR ligands in neuronal signaling. Through additional mutations, we generated a receptor antagonist with increased binding to CNTFR but lack of binding to the coreceptors that inhibited tumor progression in murine xenograft models of nonsmall cell lung cancer. These studies further validate the CLCF1–CNTFR signaling axis as a therapeutic target and highlight an approach of engineering cytokine activity through a small number of mutations.

scholarly journals Cytokine-Like Factor 1, an Essential Facilitator of Cardiotrophin-Like Cytokine:Ciliary Neurotrophic Factor Receptor α Signaling and sorLA-Mediated Turnover

2016 ◽  
Vol 36 (8) ◽  
pp. 1272-1286 ◽  
Author(s):  
Jakob Vejby Larsen ◽  
Anders Mejer Kristensen ◽  
Lone Tjener Pallesen ◽  
Johannes Bauer ◽  
Christian Bjerggaard Vægter ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Neurotrophic Factor ◽  
Leukemia Inhibitory Factor ◽  
Neuronal Development ◽  
Early Death ◽  
Ciliary Neurotrophic Factor ◽  
Leukemia Inhibitory Factor Receptor ◽  
Precise Role ◽  
Ciliary Neurotrophic Factor Receptor

Cardiotrophin-like cytokine:cytokine-like factor-1 (CLC:CLF-1) is a heterodimeric neurotropic cytokine that plays a crucial role during neuronal development. Mice lacking CLC:CLF-1 die soon after birth due to a suckling defect and show reduced numbers of motor neurons. Humans carrying mutations in CLC:CLF-1 develop similar disorders, known as Sohar-Crisponi or cold-induced sweating syndrome, and have a high risk of early death. It is well known that CLC binds the ciliary neurotrophic factor receptor α (CNTFRα) and is a prerequisite for signaling through the gp130/leukemia inhibitory factor receptor β (LIFRβ) heterodimer, whereas CLF-1 serves to promote the cellular release of CLC. However, the precise role of CLF-1 is unclear. Here, we report that CLF-1, based on its binding site for CLC and on two additional and independent sites for CNTFRα and sorLA, is a key player in CLC and CNTFRα signaling and turnover. The site for CNTFRα enables CLF-1 to promote CLC:CNTFRα complex formation and signaling. The second site establishes a link between the endocytic receptor sorLA and the tripartite CLC:CLF-1:CNTFRα complex and allows sorLA to downregulate the CNTFRα pool in stimulated cells. Finally, sorLA may bind and concentrate the tripartite soluble CLC:CLF-1:CNTFRα complex on cell membranes and thus facilitate its signaling through gp130/LIFRβ.

scholarly journals Activation and Molecular Targets of Peroxisome Proliferator-Activated Receptor-γLigands in Lung Cancer

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-8 ◽  
Author(s):  
Raphael A. Nemenoff ◽  
Mary Weiser-Evans ◽  
Robert A. Winn
Keyword(s):  
Lung Cancer ◽  
Treatment Strategies ◽  
Nonsmall Cell Lung Cancer ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Treatment And Prevention ◽  
Direct Binding ◽  
Xenograft Models ◽  
New Treatment

Lung cancer is the leading cause of cancer death, and five-year survival remains poor, raising the urgency for new treatment strategies. Activation of PPARγrepresents a potential target for both the treatment and prevention of lung cancer. Numerous studies have examined the effect of thiazolidinediones such as rosiglitazone and pioglitazone on lung cancer cells in vitro and in xenograft models. These studies indicate that activation of PPARγinhibits cancer cell proliferation as well as invasiveness and metastasis. While activation of PPARγcan occur by direct binding of pharmacological ligands to the molecule, emerging data indicate that PPARγactivation can occur through engagement of other signal transduction pathways, including Wnt signaling and prostaglandin production. Data, both from preclinical models and retrospective clinical studies, indicate that activation of PPARγmay represent an attractive chemopreventive strategy. This article reviews the existing biological and mechanistic experiments focusing on the role of PPARγin lung cancer, focusing specifically on nonsmall cell lung cancer.

Ciliary Neurotrophic Factor May Activate Mature Astrocytes via Binding with the Leukemia Inhibitory Factor Receptor

2001 ◽  
Vol 17 (2) ◽  
pp. 373-384 ◽  
Author(s):  
Christelle Monville ◽  
Muriel Coulpier ◽  
Luciano Conti ◽  
Claudio De-Fraja ◽  
Patrick Dreyfus ◽  
...  
Keyword(s):  
Neurotrophic Factor ◽  
Leukemia Inhibitory Factor ◽  
Ciliary Neurotrophic Factor ◽  
Inhibitory Factor ◽  
Leukemia Inhibitory Factor Receptor

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

2010 ◽  
Vol 30 (17) ◽  
pp. 4175-4187 ◽  
Author(s):  
Jakob Vejby Larsen ◽  
Maria Hansen ◽  
Bjarne Møller ◽  
Peder Madsen ◽  
Jürgen Scheller ◽  
...  
Keyword(s):  
Neurotrophic Factor ◽  
Leukemia Inhibitory Factor ◽  
Protein Transport ◽  
Direct Interaction ◽  
Ciliary Neurotrophic Factor ◽  
Inhibitory Factor ◽  
Leukemia Inhibitory Factor Receptor ◽  
The Family ◽  
Heterodimeric Complex

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.

Ciliary neurotrophic factor maintains the pluripotentiality of embryonic stem cells

Development ◽  
1993 ◽  
Vol 119 (3) ◽  
pp. 559-565 ◽  
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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