vascular endothelial growth factor receptor-1 signaling pathway

Definition

Target type: biologicalprocess

The series of molecular signals initiated by a ligand binding to a vascular endothelial growth factor receptor-1 (VEGFR-1) on the surface of a target cell, and ending with the regulation of a downstream cellular process, e.g. transcription. [GOC:bf, GOC:uh, Wikipedia:FLT1, Wikipedia:VEGF_receptors]

The vascular endothelial growth factor receptor-1 (VEGFR-1) signaling pathway plays a crucial role in angiogenesis, the formation of new blood vessels from pre-existing ones. It is a complex process involving multiple steps, each regulated by specific proteins and signaling molecules. Here is a detailed description of the pathway:

1. **Ligand Binding:** The process begins with the binding of VEGF-A, the primary ligand for VEGFR-1, to the receptor. This binding event initiates a cascade of intracellular signaling events.

2. **Receptor Dimerization and Autophosphorylation:** Upon ligand binding, two VEGFR-1 molecules dimerize, forming a complex. This dimerization allows for trans-autophosphorylation of tyrosine residues within the intracellular kinase domain of the receptor.

3. **Activation of Downstream Signaling Cascades:** The phosphorylated tyrosine residues on VEGFR-1 serve as docking sites for various adaptor proteins, initiating a complex network of signaling cascades.

a. **PI3K/Akt Pathway:** Phosphorylated VEGFR-1 activates phosphoinositide 3-kinase (PI3K), which in turn phosphorylates phosphatidylinositol (3,4,5)-trisphosphate (PIP3). PIP3 recruits and activates Akt, a serine/threonine kinase. Akt plays a critical role in cell survival, proliferation, and angiogenesis.

b. **MAPK Pathway:** VEGFR-1 activates the mitogen-activated protein kinase (MAPK) pathway, leading to the phosphorylation of MAP kinases such as ERK1/2. This activation is important for cell proliferation and migration.

c. **PLCγ Pathway:** VEGFR-1 can also activate phospholipase C gamma (PLCγ), which hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) into diacylglycerol (DAG) and inositol trisphosphate (IP3). IP3 triggers calcium release from intracellular stores, while DAG activates protein kinase C (PKC), further contributing to signaling events.

4. **Transcriptional Regulation:** The activated signaling pathways converge on transcription factors, such as NF-κB, STATs, and AP-1. These factors translocate to the nucleus and regulate the expression of genes involved in angiogenesis, cell survival, and other processes.

5. **Angiogenesis and Vascular Remodeling:** The activation of VEGFR-1 signaling ultimately leads to the formation of new blood vessels (angiogenesis) and remodeling of existing vasculature. This involves processes like endothelial cell proliferation, migration, and differentiation.

6. **Regulation and Feedback Mechanisms:** The VEGFR-1 signaling pathway is tightly regulated by a variety of mechanisms, including negative feedback loops, protein phosphatases, and ubiquitin ligases. These mechanisms ensure proper control and prevent excessive signaling.

In summary, the VEGFR-1 signaling pathway is a complex and tightly regulated system that plays a crucial role in vascular development, angiogenesis, and tissue repair. Its dysregulation can contribute to various pathological conditions, including cancer, diabetic retinopathy, and rheumatoid arthritis.'
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