A peptide derived from the CD loop-D helix region of ciliary neurotrophic factor (CNTF) induces neuronal differentiation and survival by binding to the leukemia inhibitory factor (LIF) receptor and common cytokine receptor chain gp130.

Ciliary neurotrophic factor (CNTF) induces neuronal differentiation and promotes the survival of various neuronal cell types by binding to a receptor complex formed by CNTF receptor α (CNTFRα), gp130, and the leukemia inhibitory factor (LIF) receptor (LIFR). The CD loop-D helix region of CNTF has been suggested to be important for the cytokine interaction with LIFR. We designed a peptide, termed cintrofin, that encompasses this region. Surface plasmon resonance analysis demonstrated that cintrofin bound to LIFR and gp130, but not to CNTFRα, with apparent KD values of 35 nM and 1.1 nM, respectively. Cintrofin promoted the survival of cerebellar granule neurons (CGNs), in which cell death was induced either by potassium withdrawal or H2O2 treatment. Cintrofin induced neurite outgrowth from CGNs, and this effect was inhibited by specific antibodies against both gp130 and LIFR, indicating that these receptors are involved in the effects of cintrofin. The C-terminal part of the peptide, corresponding to the D helix region of CNTF, was shown to be essential for the neuritogenic action of the peptide. CNTF and LIF induced neurite outgrowth in CGNs plated on laminin-coated slides. On uncoated slides, CNTF and LIF had no neuritogenic effect but were able to inhibit cintrofin-induced neuronal differentiation, indicating that cintrofin and cytokines compete for the same receptors. In addition, cintrofin induced the phosphorylation of STAT3, Akt, and ERK, indicating that it exerts cell signaling properties similar to those induced by CNTF and may be a valuable survival agent with possible therapeutic potential.

Rathje M ，Pankratova S ，Nielsen J ，Gotfryd K ，Bock E ，Berezin V ... -  《-》

CNTF/LIF/gp130 receptor complex signaling maintains a VZ precursor differentiation gradient in the developing ventral forebrain.

Gregg C ，Weiss S 《DEVELOPMENT》

Differential stimulation-induced receptor localization in lipid rafts for interleukin-6 family cytokines signaling through the gp130/leukemia inhibitory factor receptor complex.

Port MD ，Gibson RM ，Nathanson NM 《JOURNAL OF NEUROCHEMISTRY》

The N-terminal cytokine binding domain of LIFR is required for CNTF binding and signaling.

He W ，Gong K ，Smith DK ，Ip NY ... -  《FEBS LETTERS》

Differential response of neuronal cells to a fusion protein of ciliary neurotrophic factor/soluble CNTF-receptor and leukemia inhibitory factor.

März P ，Ozbek S ，Fischer M ，Voltz N ，Otten U ，Rose-John S ... -  《european journal of biochemistry》