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Cardiotrophin-like Cytokine (CLC) 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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CLC
Cardiotrophin-like
cytokine (CLC)
Cardiotrophin-like
cytokine (CLC)
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CLC
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CLF
CLF
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sCNTF R alpha
sCNTF R alpha
CLC Secretion
CLC Secretion
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CLF
CLF
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CLC
CLC
CLC
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CLC
CNTF R alpha
CNTF R alpha
CNTF R alpha
CNTF R alpha
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CLC
CLC
CLC
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CLC
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CLF
CLF
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LIF R
LIF R
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gp130
gp130
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CLC-CLF Receptor
Complex
CLC-CLF Receptor
Complex
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CNTF R alpha
CNTF R alpha
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CLC
CLC
CLC
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CLC
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CLF
CLF
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LIF R
LIF R
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gp130
gp130
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Sortilin
Sortilin
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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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CLC-sCNTF R alpha
Receptor Complex
CLC-sCNTF R alpha
Receptor Complex
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gp130
gp130
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LIF R
LIF R
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sCNTF R
alpha
sCNTF R
alpha
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CLC
CLC
CLC
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CLC
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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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gp130
gp130
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LIF R
LIF R
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CLC
CLC
CLC
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CLC
sCNTF R alpha
sCNTF R alpha
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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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Cardiotrophin-like Cytokine (CLC) Signaling Pathways

Overview of Cardiotrophin-like cytokine (CLC) Signaling Pathways

Cardiotrophin-like cytokine (CLC), also known as novel neurotrophin-1 (NNT-1) and B cell stimulatory factor-3 (BSF-3), 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), Ciliary neurotrophic factor (CNTF), Cardiotrophin-1 (CT-1), and Neuropoietin. IL-6 family cytokines are structurally related and with the exception of IL-31, they typically activate receptor complexes that include the signal-transducing gp130 receptor subunit. Like other IL-6 family cytokines, CLC is a four-helix bundle cytokine. Although it contains a signal peptide, CLC must be associated with either a second soluble cytokine receptor known as Cytokine-like factor-1 (CLF-1) or soluble CNTF R alpha to be efficiently secreted. Following secretion, the CLC:CLF-1 composite cytokine binds to the glycosylphosphatidylinositol-anchored, non-signaling CNTF R alpha receptor subunit. This complex of CLC:CLF-1 and membrane-bound CNTF R alpha or the CLC:soluble CNTF R alpha complex can then recruit the signal-transducing receptor subunits, LIF R and gp130. As both CLF-1 and LIF R were found to interact with CLC through the same site, it has been suggested that CLF-1 may be removed from the receptor complex. If this is the case, the CLC receptor complex consists of either membrane-bound or soluble CNTF R alpha , LIF R, and gp130. Sortilin, a member of the Vps10p domain family of type I transmembrane receptors, may also be part of the CLC receptor complex as it has been shown to bind to CNTF, CLC/CLF-1, and Neuropoietin with high affinity and enhance the assembly of LIF R and gp130. Following receptor complex formation, multiple intracellular signaling pathways are activated downstream of the CLC composite cytokines 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. CLC composite cytokines have been shown to support motor and sympathetic neuron survival, promote astrocyte differentiation, inhibit locomotor activity during the circadian rest period, inhibit osteoblast differentiation, and have immunomodulatory effects. Unlike CNTF, the CLC:CLF-1 composite cytokine also plays an important role during development as mice lacking CLC or CLF-1 die soon after birth due to a suckling defect that is associated with a reduction in facial motor neurons. Similarly, mutations in CLF-1 or CLC in humans are associated with a rare autosomal recessive disorder known as Crisponi/cold-induced sweating syndrome, which is characterized by musculoskeletal abnormalities, facial weakness, and suckling defects that can be lethal early in life.

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

Primary CLC-Expressing Tissues Primary Biological Effects of CLC Composite Cytokines
Embryonic skeletal muscle fibers CLC-CLF plays an important role during development
Adult tissues including the heart, liver, lymph nodes, colon, kidney, spleen, and ovary Supports motor and sympathetic neuron survival and promotes astrocyte differentiation
  May inhibit locomotor activity during the circadian rest period
  Stimulates an acute phase response, a reduction in body weight, and B cell hyperplasia in mice
  CLC-CLF mutations are associated with Crisponi or cold-induced sweating syndromes and lead to early neonatal death due to a suckling defect associated with a reduced number of facial motor nuerons and musculoskeletal abnormalities
  Inhibits osteoblast differentiation
  Overexpression of CLC stimulates B cell differentiation and antibody production

Cardiotrophin-like Cytokine (CLC) Signaling Pathways background image 1