LIF 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.

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LIF
LIF
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LIF R
LIF R
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LIF
LIF
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gp130
gp130
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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 Leukemia Inhibitory Factor (LIF) Signaling Pathways

Leukemia inhibitory factor (LIF) is a member of the IL-6 cytokine family, which also includes IL-6, IL-11, IL-27 p28/IL-30, IL-31, Oncostatin M (OSM), Cardiotrophin-like cytokine (CLC), Ciliary neurotrophic factor (CNTF), Cardiotrophin-1 (CT-1), and Neuropoietin. Like other IL-6 family cytokines, LIF is a four alpha-helix bundle cytokine that signals through a receptor complex containing the gp130 receptor subunit. LIF binds with high affinity to both LIF R and gp130, which form a heterodimeric receptor complex. Both LIF R and gp130 are signal-transducing receptor subunits that associate with the Jak family of tyrosine kinases through their intracellular domains. Activation of Jak family kinases leads to the phosphorylation of STAT family proteins, primarily STAT3 and to a lesser extent STAT1, which dimerize and translocate to the nucleus, where they regulate gene expression. In addition to Jak-STAT signaling, LIF also activates the Ras-MAPK signaling pathway, the PI 3-K-Akt signaling pathway, and the p38 and JNK MAPK pathways.

LIF is produced by numerous different cell types and plays a critical role in regulating nervous system development, stem cell pluripotency, differentiation, bone metabolism, and inflammation. It was originally identified and purified based on its ability to induce mouse myeloid leukemia M1 cell differentiation and has subsequently been shown to be involved in maintaining the pluripotency and self-renewal capacity of embryonic stem cells and increasing the self-renewal capabilities of neural stem cells. In addition, LIF has been found to have effects on the nervous, reproductive, skeletal, muscular, and endocrine systems. It has been shown to stimulate the production and survival of neurons and oligodendrocytes, facilitate successful embryo implantation, regulate bone formation and remodeling, regulate myoblast survival and differentiation, promote the differentiation of both cardiac smooth muscle cells and adipocytes, and regulate adrenocorticotropic hormone secretion. Besides these activities, LIF has also been reported to regulate inflammation, promote regulatory T cell differentiation, and induce the acute phase response in hepatocytes.

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

Primary LIF-Expressing Cells Primary Biological Effects of LIF
Astrocytes Induces the differentiation of mouse myeloid leukemia cells
Bone marrow stromal cells Maintains the pluripotency and self-renewal capacity of embryonic stem cells
Cardiac myoblasts Increases the self-renewal of neural stem cells and stimulates the production and survival of neurons and oligodendrocytes
Chondrocytes Facilitates successful endometrial implantation of an embryo
Epithelial cells Regulates myoblast differentiation and promotes their survival
Fibroblasts Promotes the differentiation of cardiac smooth cells and adipocytes
Keratinocytes Induces cardiomyocte hypertrophy
Monocytes/macrophages Regulates bone formation and remodeling
Osteoblasts Regulates the secretion of adrenocorticotropic hormone
Synoviocytes Induces the production of acute phase proteins by hepatocytes
T cells Promotes Treg differentiation and inhibits Th17 cell differentiation
  Reduces the production of pro-inflammatory cytokines and increases the production of anti-inflammatory cytokines

LIF Signaling Pathways background image 1