ERBB4 signaling pathway

Definition

Target type: biologicalprocess

The series of molecular signals initiated by binding of a ligand to the tyrosine kinase receptor ERBB4 on the surface of a cell, and ending with the regulation of a downstream cellular process, e.g. transcription. [GOC:jc, PMID:16460914, Reactome:R-HSA-1236394]

The ERBB4 signaling pathway is a complex and highly regulated cascade initiated by the binding of ligands to the ERBB4 receptor tyrosine kinase. This pathway plays a crucial role in various biological processes, including cell growth, differentiation, survival, and migration. It is implicated in various developmental processes and diseases, including cancer.

The pathway begins with the binding of neuregulins (NRGs), a family of growth factors, to the extracellular domain of ERBB4. This binding event induces receptor dimerization, bringing together two ERBB4 molecules. Dimerization activates the intrinsic tyrosine kinase activity of ERBB4, leading to autophosphorylation of specific tyrosine residues within the receptor.

Phosphorylated ERBB4 serves as a docking site for a range of intracellular signaling molecules, including adaptor proteins, phospholipases, and downstream kinases. These signaling molecules interact with specific phosphotyrosine motifs on the ERBB4 receptor, initiating downstream signaling cascades.

One major downstream pathway activated by ERBB4 is the PI3K/AKT pathway. Activated ERBB4 recruits the PI3K (phosphatidylinositol 3-kinase) to the plasma membrane. PI3K then phosphorylates PIP2 (phosphatidylinositol 4,5-bisphosphate), generating PIP3 (phosphatidylinositol 3,4,5-trisphosphate). PIP3 acts as a second messenger, recruiting AKT to the plasma membrane. AKT is a serine/threonine kinase that becomes activated by phosphorylation. Activated AKT then phosphorylates a variety of downstream targets, including mTOR (mammalian target of rapamycin), leading to increased protein synthesis and cell survival.

Another important downstream pathway activated by ERBB4 is the RAS/MAPK pathway. ERBB4 recruits GRB2 (growth factor receptor-bound protein 2) to the plasma membrane. GRB2, in turn, binds to SOS (son of sevenless) protein, a guanine nucleotide exchange factor (GEF) for RAS. SOS activates RAS by promoting the exchange of GDP for GTP, leading to RAS activation. Activated RAS activates a cascade of MAP kinases (MAPKs), including MEK (MAPK/ERK kinase) and ERK (extracellular signal-regulated kinase). The MAPK pathway regulates a wide range of cellular processes, including gene expression, proliferation, and differentiation.

In addition to these major pathways, ERBB4 also activates other signaling cascades, such as the PLCγ pathway and the JNK pathway. The PLCγ pathway leads to the production of inositol trisphosphate (IP3) and diacylglycerol (DAG), which act as second messengers to regulate calcium mobilization and protein kinase C activation. The JNK pathway is involved in stress responses and apoptosis.

The ERBB4 signaling pathway is tightly regulated by a variety of mechanisms, including feedback loops, receptor internalization, and protein degradation. These regulatory mechanisms ensure that the pathway is activated only when appropriate and that signaling is terminated once the stimulus is removed.

Dysregulation of the ERBB4 signaling pathway is implicated in a variety of diseases, including cancer. Overexpression or mutations in ERBB4 have been linked to increased tumor growth, metastasis, and resistance to therapy. As such, ERBB4 is a promising target for the development of new cancer therapies.

Overall, the ERBB4 signaling pathway is a critical regulator of cell growth, differentiation, and survival. It is involved in diverse developmental processes and diseases, and its dysregulation can lead to various pathologies. Further understanding of this pathway could lead to the development of novel therapeutic strategies for a variety of diseases.'
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Proteins (1)

Compounds (93)