CNTF Signaling
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CNTF Signaling
CNTF (Ciliary Neurotrophic Factor) is a protein expressed in glial cells, which stimulates gene expression and cell survival and differentiation in a variety of neuronal cell populations and acts as a lesion factor involved in the prevention of nerve degeneration after injury. It is a member of the GP130 (130-kDa Glycoprotein) cytokine family along with structurally related hemato- and neuropoietic cytokines IL-6 (Interleukin-6), IL-11 (Interleukin-11), LIF (Leukemia Inhibitory Factor), OSM (Oncostatin M), CT-1 (Cardiotrophin-1), Leptin and CLC (Cardiotrophin-Like Cytokine). The actions of CNTF are mediated, in part by CNTFR-Alpha (CNTF-specific Receptor). Upon translation, the C-terminus of CNTFR-Alpha is cleaved. Mature CNTFR-Alpha has no transmembrane or cytosolic domains and is found on the outer surface of the cell membrane where it is attached by a GPI Anchor (Glycosylphosphatidylinositol). CNTFR-Alpha is predominant within neural tissues, skeletal muscle, adrenal gland, sciatic nerve, skin, kidney, and testes (Ref.1).

CNTF signaling is initiated when CNTF binds CNTFR-Alpha, either in its soluble or membrane-bound form. The membrane-bound form of CNTFR (mb-CNTFR), which is anchored to the cell surface via a GPI linkage, is expressed in neuronal and skeletal muscle cells. The soluble form of CNTFR (s-CNTFR), which is produced by PLC (Phospholipase-C)-mediated cleavage of mb-CNTFR, serves as a cofactor in potentiating CNTF actions on cells that express GP130 and LIFR-Beta (LIF Receptor-Beta). 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 (Ref.2). Once a CNTF-CNTFR-Alpha complex is formed, two of these heterodimers come together and recruit a GP130 transducer protein, followed by a subsequent recruitment of LIFR-Beta protein. The resulting receptor complex is a hexamer of CNTF, CNTFR-Alpha, GP130, and LIFR in a 2:2:1:1 ratio, respectively. Within this complex, CNTF and CNTFR-Alpha make direct contacts with all the complex components. Aside from this hexameric, high affinity binding complex, CNTF can bind its receptors and can induce signaling in the absence of CNTFR-Alpha, solely by binding to a GP130: LIFR dimeric receptor (Ref.3).

CNTF-induced heterodimerization of the Beta receptor subunits of GP130 leads to tyrosine phosphorylation of JAK1/2 (Janus Kinases)/TYK2 (Protein-Tyrosine Kinase-2) complex, and the activated receptor provides docking sites for SH2-containing signaling molecules, such as SHP2 (Tyrosine Phosphatase Shp2), GRB2 (Growth Factor Receptor Bound Protein-2) and SOS . This is the starting point for a Ras /Raf/MEK (MAP/ERK Kinase)/ERK (Extracellular signal-Regulated Kinases)/p90RSK (p90 Ribosomal-S6-Kinase) cascade. The families of STATs (Signal Transducers and Activators of Transcription) 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 (Ref.4). A third alternative signaling pathway triggered by GP130 activation is the phosphorylation and activation of PI3K ( Phosphatidylinositide 3-Kinase). PI3K activates Akt kinase and plays an important role in protein synthesis via p70S6K (p70 S6 Kinase).

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. In addition to preventing neuronal degeneration in various lesion paradigms, systemically administered CNTF causes fever, acute-phase response, weight loss, and anorexia in experimental animals and humans (Ref.1). Intracerebral administration of CNTF and CNTF analogs protect striatal output neurons in rodent and primate models of Huntington’s disease. Treatment of humans and animals with CNTF induces weight loss characterized by a preferential loss of body fat. When administered systemically, CNTF activates downstream signaling molecules such as STAT3 in areas of the hypothalamus which regulate food intake.