negative regulation of ERBB signaling pathway

Definition

Target type: biologicalprocess

Any process that stops, prevents or reduces the frequency, rate or extent of ERBB signaling pathway. [GOC:BHF, GOC:TermGenie]

Negative regulation of ERBB signaling pathway is a complex and multifaceted process that involves the modulation of receptor tyrosine kinase (RTK) activity, downstream signaling cascades, and cellular responses. ERBB receptors, also known as epidermal growth factor receptors (EGFRs), are transmembrane proteins that play crucial roles in cell growth, proliferation, differentiation, and survival. Upon ligand binding, ERBB receptors undergo dimerization and autophosphorylation, leading to the activation of various signaling pathways, including the RAS/RAF/MEK/ERK pathway, the PI3K/AKT pathway, and the JAK/STAT pathway. These pathways ultimately regulate gene expression and cellular functions. Negative regulation of ERBB signaling is essential for maintaining cellular homeostasis and preventing uncontrolled cell growth and tumor development.

Several mechanisms contribute to the negative regulation of ERBB signaling:

1. **Ligand depletion:** Binding of ligands to ERBB receptors is transient, and the concentration of ligands is often tightly regulated. Ligand depletion can reduce receptor activation and downstream signaling.

2. **Receptor internalization and degradation:** Upon activation, ERBB receptors are internalized via endocytosis and trafficked to lysosomes for degradation. This process removes receptors from the cell surface and reduces signaling.

3. **Protein tyrosine phosphatases (PTPs):** PTPs are enzymes that dephosphorylate tyrosine residues on activated receptors, thereby inactivating them.

4. **Feedback inhibition:** Activated ERBB receptors can trigger the expression of negative regulators, such as Sprouty proteins, which inhibit downstream signaling.

5. **Ubiquitination and proteasomal degradation:** Ubiquitination of ERBB receptors targets them for proteasomal degradation, reducing their abundance and signaling activity.

6. **MicroRNAs (miRNAs):** miRNAs are small non-coding RNAs that can bind to the mRNAs of ERBB receptors or their downstream signaling molecules, suppressing their expression and activity.

7. **Other signaling pathways:** Cross-talk with other signaling pathways, such as the TGF-β pathway, can also inhibit ERBB signaling.

Dysregulation of negative regulation of ERBB signaling can lead to uncontrolled cell growth and tumorigenesis. Mutations in ERBB receptors, PTPs, or other negative regulators can contribute to cancer development. Conversely, promoting negative regulation of ERBB signaling can be a potential therapeutic strategy for cancer treatment.'
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Proteins (2)

Compounds (4)