regulation of platelet-derived growth factor receptor-beta signaling pathway

Definition

Target type: biologicalprocess

Any process that modulates the frequency, rate or extent of platelet-derived growth factor receptor-beta signaling pathway. [GOC:obol]

The platelet-derived growth factor receptor-beta (PDGFR-β) signaling pathway is a complex cascade that plays a crucial role in various cellular processes, including cell proliferation, migration, differentiation, and survival. The pathway is activated by the binding of platelet-derived growth factor (PDGF) to its receptor, PDGFR-β, a transmembrane tyrosine kinase receptor.

Upon PDGF binding, PDGFR-β dimerizes and undergoes autophosphorylation on specific tyrosine residues within its intracellular domain. These phosphorylated tyrosine residues serve as docking sites for various downstream signaling molecules, including adaptor proteins, kinases, and phosphatases.

The activation of PDGFR-β triggers a series of downstream signaling events, involving multiple intracellular pathways:

1. **RAS/MAPK Pathway:** Activated PDGFR-β recruits the adaptor protein GRB2, which in turn binds to SOS, a guanine nucleotide exchange factor (GEF). SOS activates the small GTPase RAS by promoting its exchange of GDP for GTP. Activated RAS further activates the MAPK (mitogen-activated protein kinase) cascade, ultimately leading to the phosphorylation and activation of transcription factors such as Elk-1 and c-Fos, which regulate gene expression.

2. **PI3K/AKT Pathway:** PDGFR-β also activates the phosphoinositide 3-kinase (PI3K) pathway. PI3K phosphorylates phosphatidylinositol (PIP2) to generate PIP3, a lipid second messenger that recruits and activates AKT (also known as protein kinase B). AKT phosphorylates and inhibits pro-apoptotic proteins like BAD, promoting cell survival, while also activating mTOR, a key regulator of protein synthesis and cell growth.

3. **PLCγ Pathway:** PDGFR-β can activate phospholipase C gamma (PLCγ), which hydrolyzes PIP2 to generate diacylglycerol (DAG) and inositol trisphosphate (IP3). DAG activates protein kinase C (PKC), while IP3 mobilizes calcium from intracellular stores, contributing to various cellular responses including cytoskeletal rearrangements and gene expression.

4. **JAK/STAT Pathway:** PDGFR-β can also activate the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. This pathway involves phosphorylation of STAT proteins by JAK kinases, leading to their dimerization and translocation to the nucleus, where they act as transcription factors.

The regulation of PDGFR-β signaling is crucial for maintaining normal cellular function and preventing uncontrolled cell growth. Dysregulation of this pathway is implicated in various diseases, including cancer, atherosclerosis, and fibrosis. The pathway is tightly controlled by a variety of mechanisms, including:

* **Negative feedback loops:** Activated PDGFR-β can trigger the recruitment of negative regulators like Sprouty and SHP2, which inhibit downstream signaling.
* **Protein phosphatases:** Phosphatases like SHP2 and PTEN dephosphorylate key signaling molecules, deactivating the pathway.
* **Ubiquitination and proteasomal degradation:** PDGFR-β can be ubiquitinated and degraded by the proteasome, limiting its activity.
* **Endocytosis:** PDGFR-β can be internalized and degraded via endocytosis, reducing its cell surface expression.

Understanding the intricate regulatory mechanisms of the PDGFR-β signaling pathway is essential for developing therapeutic strategies targeting this pathway for the treatment of various diseases.'
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Proteins (1)

Compounds (10)