Cardiotrophin-1 Signaling Pathways

Click on the other IL-6 family cytokines listed 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.

Cardiotrophin-1 (CT-1)
Cardiotrophin-1 (CT-1)
CT-1 specific
alpha chain
receptor
CT-1 specific
alpha chain
receptor
CT-1
CT-1
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LIF R
LIF R
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gp130
gp130
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CT-1 specific alpha
chain receptor
CT-1 specific alpha
chain receptor
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LIF R
LIF R
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gp130
gp130
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CT-1
CT-1
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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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OR
OR
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LIF R
LIF R
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gp130
gp130
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CT-1
CT-1
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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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MEK5
MEK5
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ERK5
ERK5
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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
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Raf
Raf
MEK1/2
MEK1/2
ERK1/2
ERK1/2
p90 RSK
p90 RSK
Transcription Factor
Transcription Factor

Overview of Cardiotrophin-1 (CT-1) Signaling Pathways

Cardiotrophin-1 (CT-1) 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), Ciliary neurotrophic factor (CNTF), and Neuropoietin. CT-1 was identified as a factor produced by mouse embryoid bodies that induced a hypertrophic response in neonatal cardiac myocytes. It was subsequently shown to promote cardiomyocyte maturation and to have cardioprotective effects. Similar to other IL-6 family cytokines, CT-1 is a four-helix bundle cytokine that signals through a receptor complex containing the gp130 receptor subunit. CT-1, like CNTF, lacks a hydrophobic signal peptide and is therefore not thought to be secreted by conventional mechanisms. CT-1 initiates intracellular signaling by binding to either a CT-1-specific alpha receptor that associates with LIF R and then recruits gp130, or by binding directly with low affinity to LIF R, which promotes its heterodimerization with gp130 and the formation of a high affinity receptor complex. Both LIF R and gp130 associate with members of the Jak family of tyrosine kinases, leading to the phosphorylation of STAT proteins, predominantly STAT1 and STAT3, which then homodimerize and translocate to the nucleus where they regulate the expression of specific target genes. In addition to the Jak-STAT pathway, CT-1 also activates the Ras-MAPK pathway, the PI 3-K-Akt pathway, the MEK5-ERK5 pathway, and the MAPKs, p38 and JNK. Besides its effects on cardiovascular tissue, CT-1 has been found to have significant protective effects on other tissues as well. In the nervous system, these effects include promoting the survival and maintenance of motor neurons during development, stimulating the development, differentiation, and survival of neural stem cells, promoting astrogenesis and gliogenesis, protecting motor, dopaminergic, and ciliary ganglion neurons against injuries and dysfunctions, and promoting myelination. In the liver, CT-1 protects against liver damage and is a potent inducer of the acute phase response. Additionally, CT-1 has been shown to regulate energy metabolism and inflammation.

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

Primary CT-1-Expressing Cells/Tissues Primary Biological Effects of CT-1
Cardiomyocytes Induces cardiomyocyte hypertrophy
Adipocytes Promotes cardiomyocyte differentiation
Fetal forebrain Has cardioprotective activity
Fetal, postnatal, and adult choroid plexus cells Stimulates the development, differentiation, and survival of neural stem cells; Promotes astrogenesis and gliogenesis
Embryonic cortex Protects motor neurons, dopaminergic neurons, and ciliary ganglion neurons against a variety of injuries and dysfunctions
Ependymal cells Has promyelinating effects
Leptomeninges Acts as a hepatoprotective molecule; Protects against liver damage
Hepatocytes Induces the acute phase response in primary hepatocytes
Hepatic non-parenchymal cells Inhibits the spontaneous differentiation of embryonic stem cells
Skeletal myocytes Regulates energy metabolism, reduces lipid accumulation, improves insulin sensitivity
  Regulates inflammation

Cardiotrophin-1 Signaling Pathways background image 1