negative regulation of insulin-like growth factor receptor signaling pathway

Definition

Target type: biologicalprocess

Any process that stops, prevents, or reduces the frequency, rate or extent of insulin-like growth factor receptor signaling. [GOC:bf]

The negative regulation of insulin-like growth factor receptor (IGF-R) signaling pathway involves a complex network of molecular interactions that dampen the growth-promoting and metabolic effects of IGF-R activation. This process is crucial for maintaining cellular homeostasis, preventing uncontrolled cell proliferation, and ensuring proper development. Here's a detailed breakdown of the key mechanisms involved:

**1. Receptor Internalization and Degradation:**

* IGF-R activation triggers its internalization through clathrin-mediated endocytosis.
* Once internalized, the receptor can either be recycled back to the cell surface or targeted for degradation in lysosomes.
* Ubiquitination plays a critical role in this process, tagging the receptor for endocytosis and lysosomal degradation.

**2. Ligand Binding Inhibition:**

* Proteins like IGF-binding proteins (IGFBPs) can sequester IGF ligands in the extracellular space, preventing their interaction with IGF-R.
* This reduces the concentration of free IGF ligands available for binding to the receptor.

**3. Negative Feedback Loops:**

* Upon activation, IGF-R triggers the phosphorylation of downstream signaling molecules, including the insulin receptor substrate (IRS) proteins.
* These phosphorylated IRS proteins can activate negative regulators, such as the protein tyrosine phosphatase (PTP) family members, leading to the dephosphorylation and inactivation of IGF-R and its downstream signaling components.

**4. Inhibition of Signal Transduction Cascades:**

* Specific phosphatases, like SHP-1 and SHP-2, directly dephosphorylate IGF-R, preventing its activation.
* Other negative regulators, such as suppressor of cytokine signaling (SOCS) proteins, inhibit downstream signaling molecules like JAK kinases, thus disrupting the IGF-R signaling cascade.

**5. MicroRNA Regulation:**

* MicroRNAs (miRNAs) can fine-tune IGF-R signaling by targeting specific mRNA transcripts involved in IGF-R signaling.
* Certain miRNAs can downregulate the expression of IGF-R or its downstream effectors, reducing overall pathway activity.

**6. Cellular Context-Specific Regulation:**

* The negative regulation of IGF-R signaling can vary depending on the cell type, developmental stage, and environmental cues.
* This context-dependent regulation ensures that the pathway is appropriately modulated to meet the specific needs of the cell and tissue.

These interconnected mechanisms contribute to the precise and dynamic regulation of IGF-R signaling, preventing excessive growth, ensuring appropriate metabolic control, and promoting cellular health.'
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Proteins (2)

Compounds (9)