CNTF Signaling


Pathway Description

Ciliary Neurotrophic Factor (CNTF) is a protein produced by glial cells that stimulates gene expression, cell survival, and differentiation in a variety of neuronal cell populations. CNTF also acts as a lesion factor involved in the prevention of nerve degeneration after injury. It is a member of the GP130 cytokine family along with structurally related hemato- and neuropoietic cytokines such as IL-6, IL-11, LIF, Oncostatin M, Cardiotrophin-1, Leptin and Cardiotrophin-Like Cytokine. The actions of CNTF are mediated in part by CNTFR-α. Upon translation, the C-terminus of CNTFR-α is cleaved.CNTF signaling is initiated when CNTF binds CNTFR-α, either in its soluble (s) or membrane-bound (mb) form. The soluble form of CNTFR (s-CNTFR), which is produced by Phospholipase-C (PLC)-mediated cleavage of mb-CNTFR, serves as a cofactor in potentiating CNTF actions on cells that express GP130 and LIFR-β. Soluble CNTFR is found in cerebrospinal fluid and serum and is involved in mediating some of the non-neuronal actions of CNTF such as hepatic acute phase response. Once a CNTF-CNTFR-α complex is formed, two of these heterodimers come together and recruit a GP130 transducer protein, followed by a subsequent recruitment of LIFR-β. Aside from this hexameric, high affinity binding complex, CNTF can bind its receptors and can induce signaling in the absence of CNTFR-α, solely by binding to a GP130:LIFR dimeric receptor.

CNTF-induced heterodimerization of the β receptor subunits of GP130 leads to tyrosine phosphorylation of JAK1/TYK2 and JAK2/TYK2 complexes, and the activated receptors provide docking sites for SH2-containing signaling molecules, such as SHP2, GRB2 and SOS. This is the starting point for a Ras/Raf/MEK/ERK/p90 Ribosomal-S6-Kinase (p90RSK) cascade. The families of STATs are also SH2 domain containing factors that are able to bind to the phosphorylated GP130. They subsequently dimerize and translocate to the nucleus to bind specific DNA sequences, resulting in enhanced transcription of responsive genes. A third signaling pathway triggered by GP130 activation is the phosphorylation and activation of PI3K. PI3K activates Akt kinase and plays an important role in protein synthesis via p70S6K.

In addition to its neuronal actions, CNTF can also elicit biological effects in non-neuronal cells such as hepatocytes, skeletal muscle cells, embryonic stem cells, bone marrow stromal cells, and tumor plasma cells. Human CNTF is a neurotrophic cytokine that exerts a neuroprotective effect in multiple sclerosis and amyotrophic lateral sclerosis. CNTF also prevents neuronal degeneration in various lesion paradigms, but it does have several side effects when systemically administered, including fever, acute-phase response, weight loss (specifically body fat loss), and anorexia in experimental animals and humans. Intracerebral administration of CNTF and analogs protect striatal output neurons in rodent and primate models of Huntington's disease. When administered systemically, CNTF activates downstream signaling molecules such as STAT3 in areas of the hypothalamus that regulate food intake.