title: Cytokine-Like Factor 1, an Essential Facilitator of Cardiotrophin-Like Cytokine:Ciliary Neurotrophic Factor Receptor α Signaling and sorLA-Mediated Turnover.
abstract: 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.
authors: The MIND Center, Department of Biomedicine, Aarhus University, Aarhus, Denmark jvl@biomed.au.dk cmp@biomed.au.dk.
authors: Jakob Vejby
authors: JV
authors: Larsen
authors: The MIND Center, Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors: Anders Mejer
authors: AM
authors: Kristensen
authors: The MIND Center, Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors: Lone Tjener
authors: LT
authors: Pallesen
authors: The MIND Center, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
authors: Johannes
authors: J
authors: Bauer
authors: The MIND Center, Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors: Christian Bjerggaard
authors: CB
authors: Vægter
authors: The MIND Center, Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors: Morten Schallburg
authors: MS
authors: Nielsen
authors: The MIND Center, Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors: Peder
authors: P
authors: Madsen
authors: The MIND Center, Department of Biomedicine, Aarhus University, Aarhus, Denmark jvl@biomed.au.dk cmp@biomed.au.dk.
authors: Claus Munck
authors: CM
authors: Petersen
mesh_terms: D053739:Ciliary Neurotrophic Factor Receptor alpha Subunit / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D011485:Protein Binding; D018121:Receptors, Cytokine / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D053739:Ciliary Neurotrophic Factor Receptor alpha Subunit; D016207:Cytokines; D026502:LDL-Receptor Related Proteins; D026901:Membrane Transport Proteins; D018121:Receptors, Cytokine; C102582:SORL1 protein, human; C121169:cardiotrophin-like cytokine; C113554:cytokine-like factor-1