leukemia inhibitory factor signaling pathway

Definition

Target type: biologicalprocess

The series of molecular signals initiated by the binding of a leukemia inhibitory factor to its receptor on the surface of a target cell, and ending with the regulation of a downstream cellular process, e.g. transcription. [GOC:devbiol, GOC:signaling]

Leukemia inhibitory factor (LIF) signaling is a crucial pathway involved in various cellular processes, including cell growth, differentiation, survival, and inflammation. It plays a significant role in the development and maintenance of several tissues, particularly in the nervous, immune, and reproductive systems. Here is a detailed description of the LIF signaling pathway:

**1. Ligand Binding and Receptor Activation:**

* LIF, a pleiotropic cytokine, binds to its receptor complex, composed of the LIF receptor (LIFR) and the glycoprotein 130 (gp130).
* Binding of LIF to the receptor complex initiates dimerization of LIFR and gp130.
* Dimerization triggers the activation of the intracellular tyrosine kinase domains associated with both receptors.

**2. JAK/STAT Signaling Cascade:**

* Activated tyrosine kinases, Janus kinases (JAKs), primarily JAK1 and JAK2, phosphorylate tyrosine residues on the cytoplasmic tails of LIFR and gp130.
* Phosphorylated tyrosine residues serve as docking sites for signal transducer and activator of transcription (STAT) proteins, specifically STAT3.
* STAT3 binds to the phosphorylated receptors and is itself phosphorylated by JAKs.
* Phosphorylated STAT3 dimerizes and translocates to the nucleus.

**3. Transcriptional Regulation:**

* In the nucleus, dimerized STAT3 binds to specific DNA sequences known as STAT-binding elements (SBE) located in the promoter regions of target genes.
* Binding of STAT3 to SBE activates transcription of genes involved in various cellular processes, including cell proliferation, differentiation, and survival.
* Some of the key genes regulated by LIF signaling include suppressor of cytokine signaling (SOCS), Bcl-2, and c-Fos.

**4. Feedback Inhibition:**

* The LIF signaling pathway is subject to negative feedback regulation through the induction of SOCS proteins.
* SOCS proteins act as inhibitors of JAK activity, preventing further phosphorylation of STAT3 and limiting the duration of the signaling pathway.
* This feedback mechanism helps maintain homeostasis and prevents excessive activation of the pathway.

**5. Biological Functions:**

* **Embryonic development:** LIF plays a critical role in embryo implantation, blastocyst development, and early embryonic patterning.
* **Hematopoiesis:** LIF promotes the differentiation of hematopoietic stem cells into various blood cell lineages.
* **Neurogenesis:** LIF regulates neuronal survival, differentiation, and plasticity in the central nervous system.
* **Immune response:** LIF modulates the immune response by regulating cytokine production and immune cell function.
* **Inflammation:** LIF has both pro-inflammatory and anti-inflammatory effects, depending on the context.

**6. Clinical Relevance:**

* LIF deficiency can lead to developmental defects, impaired immune function, and neurological disorders.
* LIF signaling is implicated in various diseases, including cancer, autoimmune disorders, and neurodegenerative diseases.
* LIF and its agonists are being investigated as potential therapeutic agents for a variety of conditions.

This comprehensive description provides insights into the intricate molecular mechanisms of LIF signaling and its diverse biological roles. The pathway's involvement in various cellular processes highlights its importance in maintaining normal physiological function and its potential as a target for therapeutic interventions.'
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Proteins (1)

Compounds (2)