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

Larsen JV, Kristensen AM, Pallesen LT, Bauer J, Vægter CB, Nielsen MS, Madsen P, Petersen CM - Mol. Cell. Biol. (2016)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: The MIND Center, Department of Biomedicine, Aarhus University, Aarhus, Denmark jvl@biomed.au.dk cmp@biomed.au.dk.

No MeSH data available.


Related in: MedlinePlus

Model of the interplay between CLC, CLF-1, CNTFRα, and sorLA. (A) The cytokine subunits CLC and CLF-1 each contain a single site for CNTFRα binding and bind with moderate affinity (thin arrows). The assembled heterodimer CLC:CLF-1 contains two binding sites (one in each subunit), which together generate a bonus effect and a high affinity for CNTFRα (thick arrow). CLF-1 further harbors an independent site for binding to sorLA and binds sorLA alone or in complex with other subunits. (B) sorLA conveys endocytosis of the tripartite complex CLC:CLF-1:CNTFRα via binding to CLF-1. Following internalization, CNTFRα and CLC:CLF-1 are sorted to lysosomal degradation while sorLA is recycled. (C) sorLA may enhance signaling, notably in CNTFRα-deficient cells, by binding and concentrating complexes of CLC:CLF-1 and sCNTFRα on the cell membrane.
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Figure 9: Model of the interplay between CLC, CLF-1, CNTFRα, and sorLA. (A) The cytokine subunits CLC and CLF-1 each contain a single site for CNTFRα binding and bind with moderate affinity (thin arrows). The assembled heterodimer CLC:CLF-1 contains two binding sites (one in each subunit), which together generate a bonus effect and a high affinity for CNTFRα (thick arrow). CLF-1 further harbors an independent site for binding to sorLA and binds sorLA alone or in complex with other subunits. (B) sorLA conveys endocytosis of the tripartite complex CLC:CLF-1:CNTFRα via binding to CLF-1. Following internalization, CNTFRα and CLC:CLF-1 are sorted to lysosomal degradation while sorLA is recycled. (C) sorLA may enhance signaling, notably in CNTFRα-deficient cells, by binding and concentrating complexes of CLC:CLF-1 and sCNTFRα on the cell membrane.

Mentions: Following preexposure to CLC:CLF-1 (and sorLA-mediated downregulation of CNTFRα), the cellular response to renewed CLC:CLF-1 stimulation was significantly reduced in wt cells with endogenous expression of CNTFRα and sorLA and even more so in transfectants overexpressing sorLA. Thus, sorLA may have a profound effect on the cellular response under conditions of constant exposure to ligand (CLC:CLF-1), but apart from that, sorLA did not directly influence signaling; i.e., it neither enhanced nor hampered interaction with the gp130/LIFRβ heterodimer in CNTFRα-expressing cells. However, in cells expressing gp130/LIFRβ but not CNTFRα, expression of sorLA enhanced signaling (pSTAT3) in response to sCNTFRα in complex with CLC:CLF-1 but not to the CLC-sCNTFRα fusion protein complex, which does not bind sorLA. These results suggest that in cells without membrane-expressed CNTFRα, sorLA may bind and concentrate the tripartite soluble complex (CLC:CLF-1:sCNTFRα) on the cell membrane and in this way promote interaction with gp130/LIFRβ and thereby signaling. A previous study based on molecular modeling reported an overlap between CLC's binding sites for CLF-1 and LIFRβ, suggesting that CLF-1 has to be dissociated/removed to allow signaling, i.e., interaction between CLC and LIFRβ. However, we have recently generated a CLC–linker peptide–CLF-1 fusion protein (unpublished data) which binds both CNTFRα and sorLA and which is fully capable of signal induction. Since this indicates that CLF-1 may well be part of the signaling complex, we have included it in our proposed model (Fig. 9C).


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

Larsen JV, Kristensen AM, Pallesen LT, Bauer J, Vægter CB, Nielsen MS, Madsen P, Petersen CM - Mol. Cell. Biol. (2016)

Model of the interplay between CLC, CLF-1, CNTFRα, and sorLA. (A) The cytokine subunits CLC and CLF-1 each contain a single site for CNTFRα binding and bind with moderate affinity (thin arrows). The assembled heterodimer CLC:CLF-1 contains two binding sites (one in each subunit), which together generate a bonus effect and a high affinity for CNTFRα (thick arrow). CLF-1 further harbors an independent site for binding to sorLA and binds sorLA alone or in complex with other subunits. (B) sorLA conveys endocytosis of the tripartite complex CLC:CLF-1:CNTFRα via binding to CLF-1. Following internalization, CNTFRα and CLC:CLF-1 are sorted to lysosomal degradation while sorLA is recycled. (C) sorLA may enhance signaling, notably in CNTFRα-deficient cells, by binding and concentrating complexes of CLC:CLF-1 and sCNTFRα on the cell membrane.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 9: Model of the interplay between CLC, CLF-1, CNTFRα, and sorLA. (A) The cytokine subunits CLC and CLF-1 each contain a single site for CNTFRα binding and bind with moderate affinity (thin arrows). The assembled heterodimer CLC:CLF-1 contains two binding sites (one in each subunit), which together generate a bonus effect and a high affinity for CNTFRα (thick arrow). CLF-1 further harbors an independent site for binding to sorLA and binds sorLA alone or in complex with other subunits. (B) sorLA conveys endocytosis of the tripartite complex CLC:CLF-1:CNTFRα via binding to CLF-1. Following internalization, CNTFRα and CLC:CLF-1 are sorted to lysosomal degradation while sorLA is recycled. (C) sorLA may enhance signaling, notably in CNTFRα-deficient cells, by binding and concentrating complexes of CLC:CLF-1 and sCNTFRα on the cell membrane.
Mentions: Following preexposure to CLC:CLF-1 (and sorLA-mediated downregulation of CNTFRα), the cellular response to renewed CLC:CLF-1 stimulation was significantly reduced in wt cells with endogenous expression of CNTFRα and sorLA and even more so in transfectants overexpressing sorLA. Thus, sorLA may have a profound effect on the cellular response under conditions of constant exposure to ligand (CLC:CLF-1), but apart from that, sorLA did not directly influence signaling; i.e., it neither enhanced nor hampered interaction with the gp130/LIFRβ heterodimer in CNTFRα-expressing cells. However, in cells expressing gp130/LIFRβ but not CNTFRα, expression of sorLA enhanced signaling (pSTAT3) in response to sCNTFRα in complex with CLC:CLF-1 but not to the CLC-sCNTFRα fusion protein complex, which does not bind sorLA. These results suggest that in cells without membrane-expressed CNTFRα, sorLA may bind and concentrate the tripartite soluble complex (CLC:CLF-1:sCNTFRα) on the cell membrane and in this way promote interaction with gp130/LIFRβ and thereby signaling. A previous study based on molecular modeling reported an overlap between CLC's binding sites for CLF-1 and LIFRβ, suggesting that CLF-1 has to be dissociated/removed to allow signaling, i.e., interaction between CLC and LIFRβ. However, we have recently generated a CLC–linker peptide–CLF-1 fusion protein (unpublished data) which binds both CNTFRα and sorLA and which is fully capable of signal induction. Since this indicates that CLF-1 may well be part of the signaling complex, we have included it in our proposed model (Fig. 9C).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: The MIND Center, Department of Biomedicine, Aarhus University, Aarhus, Denmark jvl@biomed.au.dk cmp@biomed.au.dk.

No MeSH data available.


Related in: MedlinePlus