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CNTF Signaling Pathways

Click on the other IL-6 family cytokines shown in the Explore Pathways box below to see the signaling pathways that are activated by each cytokine. Refer to the table below each pathway to see a select list of cytokine-expressing cells or tissues and the primary biological effects induced by the different members of the IL-6 cytokine family.

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CNTF
CNTF
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sCNTF R alpha
sCNTF R alpha
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CNTF
CNTF
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OR
OR
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sIL-6 R alpha
sIL-6 R alpha
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CNTF
CNTF
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Trans Signaling
Trans Signaling
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LIF R
LIF R
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gp130
gp130
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CNTF
CNTF
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sCNTF R alpha or
sIL-6 R alpha
sCNTF R alpha or
sIL-6 R alpha
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LIF R
LIF R
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gp130
gp130
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CNTF
CNTF
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sCNTF R alpha or
sIL-6 R alpha
sCNTF R alpha or
sIL-6 R alpha
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Sortilin
Sortilin
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sIL-6 R alpha
sIL-6 R alpha
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CNTF
CNTF
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OR
OR
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sCNTF R alpha
sCNTF R alpha
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CNTF
CNTF
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CNTF
CNTF
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Tyk2
Tyk2
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Jak2
Jak2
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Jak1
Jak1
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Tyk2
Tyk2
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Jak2
Jak2
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Jak1
Jak1
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CNTF Signaling
CNTF Signaling
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Classic Signaling
Classic Signaling
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CNTF R alpha
CNTF R alpha
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CNTF
CNTF
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OR
OR
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IL-6 R alpha
IL-6 R alpha
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CNTF
CNTF
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LIF R
LIF R
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gp130
gp130
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CNTF
CNTF
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CNTF R alpha or
IL-6 R alpha
CNTF R alpha or
IL-6 R alpha
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LIF R
LIF R
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gp130
gp130
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CNTF
CNTF
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CNTF R alpha or
IL-6 R alpha
CNTF R alpha or
IL-6 R alpha
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Sortilin
Sortilin
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IL-6 R alpha
IL-6 R alpha
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CNTF
CNTF
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OR
OR
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CNTF R alpha
CNTF R alpha
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CNTF
CNTF
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Tyk2
Tyk2
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Jak2
Jak2
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Jak1
Jak1
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Tyk2
Tyk2
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Jak2
Jak2
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Jak1
Jak1
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IRS1/2
IRS1/2
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SHP-2
SHP-2
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Grb2
Grb2
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SOS
SOS
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Gab1/2
Gab1/2
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PI 3-K
PI 3-K
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PIP2
PIP2
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PIP3
PIP3
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PDK-1
PDK-1
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Akt/PKB
Akt/PKB
Cell Survival
Cell Proliferation
Cell Survival
Cell Proliferation
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TSC1/2
(Inactive)
TSC1/2
(Inactive)
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Rheb
Rheb
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GTP
GTP
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mTORC1
mTORC1
p70 S6K
p70 S6K
RPS6
RPS6
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4EBP1
4EBP1
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eIF4E
eIF4E
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eIF4E
eIF4E
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4EBP1
4EBP1
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Protein Synthesis
Protein Synthesis
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STAT1
STAT1
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STAT3
STAT3
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STAT5
STAT5
STAT Dimer
STAT Dimer
STAT Dimer
STAT Dimer
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SHP-2 or SHC
SHP-2 or SHC
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Grb2
Grb2
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SOS
SOS
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Gab1/2
Gab1/2
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Vav
Vav
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Rac1
Rac1
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MAPKKK
(Unknown)
MAPKKK
(Unknown)
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MKK-4
MKK-4
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p38
p38
JNK
JNK
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PKC delta
PKC delta
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AP-1
AP-1
Cell Proliferation
Cell Proliferation
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Ras
Ras
Ras
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Ras
Raf
Raf
MEK1/2
MEK1/2
ERK1/2
ERK1/2
p90 RSK
p90 RSK
Transcription Factor
Transcription Factor
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CNTF Signaling Pathways

Overview of Ciliary Neurotrophic Factor (CNTF) Signaling Pathways

Ciliary neurotrophic factor (CNTF) is a member of the IL-6 cytokine family, which also includes IL-6, IL-11, IL-27 p28/IL-30, IL-31, Leukemia inhibitory factor (LIF), Oncostatin M (OSM), Cardiotrophin-like cytokine (CLC), Cardiotrophin-1 (CT-1), and Neuropoietin. CNTF is a four-helix bundle cytokine that is expressed by Schwann cells, astrocytes, and T cells. It was identified as a trophic factor for embryonic chick ciliary neurons and subsequent studies have shown that it is a survival factor for dorsal root ganglion sensory neurons, sympathetic ganglion neurons, embryonic motor neurons, and hippocampal neurons. Additionally, CNTF has been shown to promote the survival and maturation of oligodendrocytes, to induce astrocyte differentiation of glial progenitors, to have neuroprotective effects following nervous system injury and in demyelinating neurological diseases, as well as protective and regenerative effects on denervated and intact skeletal muscle, and immunomodulatory effects. CNTF knockout mice have a mild phenotype characterized by the progressive loss of motor neurons, reduced bone length, and reduced muscular strength in adult mice, but no obvious developmental defects, suggesting that unlike CLC and CLF-1, CNTF is not required for normal physiological development.

Due to its lack of a signal peptide, CNTF is thought to be a cytoplasmic molecule that is released by damaged cells. Upon its release, CNTF binds to either a glycosylphosphatidylinositol-anchored, non-signaling CNTF R alpha receptor subunit or a non-signaling IL-6 R alpha receptor subunit, which then recruits the signal-transducing receptor subunits, LIF R and gp130, to form a tripartite receptor complex. Assembly of the LIF R:gp130 heterodimer is enhanced by Sortilin, a member of the Vps10p domain family of type I transmembrane receptors, which binds to CNTF, CLC/CLF-1, and Neuropoietin with high affinity. In addition to the CNTF classic signaling pathway which occurs in cells expressing membrane-bound CNTF R alpha or IL-6 R alpha, LIF R, and gp130, CNTF can also initiate trans-signaling in cells expressing LIF R and gp130 by binding to a soluble form of CNTF R alpha or a soluble form of IL-6 R alpha. Soluble CNTF R alpha is generated following its release from the cell surface by phosphatidylinositol-specific phospholipase C, while soluble IL-6 R alpha can be generated by either alternative splicing or proteolytic cleavage. CNTF bound to the soluble forms of CNTF R alpha or IL-6 R alpha promotes the heterodimerization of LIF R and gp130, allowing a wider range of cells to respond to CNTF. Formation of either the classic or trans-signaling CNTF receptor complex triggers the activation of multiple intracellular signaling pathways including the Jak-STAT pathway, the Ras-MAPK pathway, the PI 3-K-Akt pathway, and the p38 and JNK MAPK pathways, which mediate various biological effects in different cell types.

To learn more, please visit our IL-6 Family Research Area page.

Primary CNTF-Expressing Cells Primary Biological Effects of CNTF
Astrocytes Supports the survival of a variety of neuronal cell types including sensory, sympathetic, ciliary, and motor neurons
Schwann cells Promotes the differentiation of glial progenitors into astrocytes
T cells Promotes the maturation and survival of oligodendrocytes
  Protects neuronal and glial cells following nervous system injury
  Promotes the viability of muscle progenitor cells; Has protective and regenerative neuromuscular effects
  Regulates muscle strength in aging
  Regulates the production of IFN-gamma by CD4+ T cells
  Induces the acute phase response in the liver

CNTF Signaling Pathways background image 1