ciliary neurotrophic factor-mediated signaling pathway

Definition

Target type: biologicalprocess

The series of molecular signals initiated by the binding of a ciliary neurotrophic factor (CNTF) to its receptor on the surface of a target cell, and ending with the regulation of a downstream cellular process, e.g. transcription. [GOC:BHF, GOC:mah]

Ciliary neurotrophic factor (CNTF) is a pleiotropic cytokine that plays a crucial role in the development and survival of various cell types, particularly neurons. Its signaling pathway involves a complex cascade of events that ultimately lead to the activation of downstream target genes responsible for cell survival, differentiation, and neuroprotection.

The CNTF signaling pathway begins with the binding of CNTF to its receptor complex, which consists of three components: CNTF receptor alpha (CNTFRα), gp130, and LIF receptor (LIFR). CNTFRα acts as the specific binding subunit for CNTF, while gp130 and LIFR are shared by other members of the interleukin-6 (IL-6) family of cytokines.

Upon CNTF binding, CNTFRα undergoes a conformational change, bringing together gp130 and LIFR to form a heterotrimeric receptor complex. This complex activates the associated Janus kinase (JAK) family of tyrosine kinases, specifically JAK1 and JAK2. Activated JAKs phosphorylate tyrosine residues on the cytoplasmic tails of gp130 and LIFR, creating docking sites for signal transducer and activator of transcription (STAT) proteins.

STAT proteins, including STAT3, STAT5, and STAT1, bind to phosphorylated gp130 and LIFR, becoming themselves phosphorylated by JAKs. Phosphorylated STATs dimerize and translocate to the nucleus, where they act as transcription factors, binding to specific DNA sequences called STAT response elements (REs) located within the promoter regions of target genes.

CNTF-mediated signaling activates a diverse array of genes involved in cell survival, differentiation, and neuroprotection. These genes include anti-apoptotic proteins, growth factors, and neurotrophic factors, such as BDNF, GDNF, and NT-3. The activation of these genes ultimately contributes to the survival and maintenance of neuronal cells, promoting their growth and function.

In addition to STAT activation, CNTF signaling can also activate other downstream signaling pathways, including the mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. These pathways further contribute to the pleiotropic effects of CNTF, regulating cell proliferation, differentiation, and survival.

The CNTF signaling pathway is tightly regulated by a variety of mechanisms, including the expression levels of CNTF, its receptor components, and downstream signaling molecules. Dysregulation of this pathway has been implicated in a number of neurological disorders, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and Parkinson's disease. Targeting the CNTF signaling pathway may provide therapeutic opportunities for these and other neurodegenerative diseases.'
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Proteins (1)

Compounds (2)