negative regulation of GDF15-GFRAL signaling pathway

Definition

Target type: biologicalprocess

Any process that stops, prevents or reduces the frequency, rate or extent of GDF15-GFRAL signaling pathway. [PMID:35177851]

Negative regulation of GDF15-GFRAL signaling pathway involves a complex interplay of molecular mechanisms that modulate the activity of GDF15, its receptor GFRAL, and downstream signaling cascades. This process plays a crucial role in maintaining cellular homeostasis and preventing aberrant cell growth and proliferation.

**1. GDF15 Production and Secretion:** GDF15, a member of the transforming growth factor-beta (TGF-beta) superfamily, is primarily produced by various cell types in response to cellular stress, such as hypoxia, oxidative stress, and inflammation.

**2. GDF15-GFRAL Interaction:** GDF15 binds to its specific receptor, GFRAL, a transmembrane protein expressed on various cell types. This binding initiates signal transduction, ultimately leading to the activation of intracellular signaling pathways.

**3. Negative Regulation Mechanisms:**

* **Inhibition of GDF15 Production:** Factors that suppress GDF15 synthesis can negatively regulate the pathway. For instance, certain growth factors and cytokines can downregulate GDF15 gene expression, thereby reducing its availability for signaling.
* **Blocking GDF15-GFRAL Interaction:** Molecules that interfere with the binding of GDF15 to GFRAL can disrupt signaling. These may include:
* **Soluble GFRAL:** This secreted form of GFRAL acts as a decoy receptor by competing with cell surface GFRAL for GDF15 binding.
* **Antibodies:** Antibodies targeting GDF15 or GFRAL can block their interaction, inhibiting signal transduction.
* **Downstream Signal Inhibition:** Components of the downstream signaling pathways activated by GDF15-GFRAL interaction can be negatively regulated. This may involve:
* **Phosphatases:** Enzymes that remove phosphate groups from signaling proteins, thereby deactivating them.
* **Inhibitory Proteins:** Specific proteins that bind to and inactivate signaling molecules, such as kinases or transcription factors.
* **MicroRNAs:** Small non-coding RNAs that target and suppress the expression of mRNAs involved in GDF15-GFRAL signaling.

**4. Consequences of Negative Regulation:** Decreased GDF15-GFRAL signaling can lead to:

* **Reduced Cellular Stress Responses:** By dampening the signal initiated by GDF15, cells may become less responsive to stress conditions, potentially leading to cellular dysfunction or death.
* **Enhanced Cell Growth and Proliferation:** The negative regulation of the pathway can promote cell division and proliferation, which may be beneficial in certain contexts but can also contribute to tumorigenesis if uncontrolled.
* **Altered Metabolic Processes:** GDF15-GFRAL signaling is implicated in metabolic regulation, and its negative modulation can affect energy expenditure, glucose metabolism, and appetite control.

**In summary, negative regulation of GDF15-GFRAL signaling is a critical process for maintaining cellular homeostasis and ensuring appropriate responses to various stimuli. Disruption of this pathway can lead to various pathological conditions.**'"

Proteins (1)

Compounds (26)