ERBB4-ERBB4 signaling pathway

Definition

Target type: biologicalprocess

The series of molecular signals initiated by binding of a ligand to the tyrosine kinase receptor ERBB4, followed by ligand-induced homodimerization of ERBB4 and transmission of the signal into the cell by the homodimeric ERBB4 complex. The pathway ends with regulation of a downstream cellular process, e.g. transcription. [GOC:signaling, PMID:16460914, Reactome:R-HSA-1250220]

The ERBB4-ERBB4 signaling pathway is a complex and intricate process involved in a wide range of biological functions, including cell growth, proliferation, differentiation, and survival. This pathway is activated by the binding of neuregulin (NRG) ligands, specifically NRG1 and NRG2, to the ERBB4 receptor tyrosine kinase.

Here's a detailed breakdown of the ERBB4-ERBB4 signaling pathway:

1. **Ligand Binding and Receptor Dimerization:** The process begins with NRG ligands binding to the extracellular domain of ERBB4 receptors. This binding event triggers a conformational change in the receptor, promoting dimerization of two ERBB4 molecules.

2. **Autophosphorylation and Activation:** Upon dimerization, the intracellular tyrosine kinase domains of the ERBB4 receptors become activated. This activation involves a process called autophosphorylation, where the tyrosine kinase domains of the receptors phosphorylate each other on specific tyrosine residues within their cytoplasmic tails.

3. **Recruitment of Signaling Adapters:** The phosphorylated tyrosine residues on ERBB4 act as docking sites for a variety of signaling adaptor proteins, including:
* **Shc:** This adaptor protein binds to phosphorylated ERBB4 and activates the Ras/MAPK pathway, leading to downstream effects on gene transcription, cell growth, and proliferation.
* **Grb2:** This adaptor protein also binds to phosphorylated ERBB4 and activates the Ras/MAPK pathway, contributing to cell growth and proliferation.
* **PI3K:** This enzyme binds to phosphorylated ERBB4 and activates the PI3K/Akt pathway, regulating cell survival and metabolism.

4. **Downstream Signaling Cascades:** Once the signaling adaptors are recruited, they activate downstream signaling cascades, including:
* **Ras/MAPK Pathway:** This pathway is activated by Shc and Grb2 and involves a series of protein kinases, including Ras, Raf, MEK, and ERK. The MAPK pathway regulates gene expression, cell cycle progression, and cellular differentiation.
* **PI3K/Akt Pathway:** This pathway is activated by PI3K and involves the protein kinase Akt. The PI3K/Akt pathway promotes cell survival, growth, and metabolism.

5. **Transcriptional Regulation:** The activated MAPK and PI3K/Akt pathways converge on transcription factors, such as AP-1 and NF-κB, which regulate the expression of genes involved in cell growth, survival, and differentiation.

6. **Regulation and Termination:** The ERBB4-ERBB4 signaling pathway is tightly regulated to prevent excessive or uncontrolled signaling. This regulation involves:
* **Internalization and Degradation:** After activation, ERBB4 receptors are internalized into the cell and degraded by lysosomes, limiting the duration of signaling.
* **Negative Feedback Loops:** Feedback loops involving phosphatases and other signaling molecules can dephosphorylate ERBB4 receptors and downregulate their activity.

**Biological Functions of ERBB4-ERBB4 Signaling:**

The ERBB4-ERBB4 signaling pathway plays a critical role in a wide range of biological processes, including:

* **Neural Development and Function:** This pathway is essential for the development and function of the nervous system, particularly in the regulation of synapse formation, neuronal survival, and myelination.
* **Cardiovascular Development:** The pathway contributes to heart development and function, regulating heart growth, contractility, and vascularization.
* **Breast and Prostate Cancer:** ERBB4 dysregulation has been implicated in the development and progression of certain cancers, including breast and prostate cancer.
* **Other Biological Processes:** This pathway also plays roles in immune system regulation, wound healing, and tissue regeneration.

The ERBB4-ERBB4 signaling pathway is a complex and multifaceted process that is essential for normal cellular function. Dysregulation of this pathway can contribute to various diseases, underscoring its significance in human health.'
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Proteins (1)

Compounds (93)