regulation of endothelial cell chemotaxis to fibroblast growth factor

Definition

Target type: biologicalprocess

Any process that modulates the frequency, rate or extent of endothelial cell chemotaxis to fibroblast growth factor. [GOC:obol]

Endothelial cell chemotaxis to fibroblast growth factor (FGF) is a crucial process in angiogenesis, the formation of new blood vessels. It involves a series of events orchestrated by complex signaling pathways that regulate cell migration, proliferation, and survival. Here's a detailed breakdown of the process:

1. **FGF Binding and Receptor Activation:** The process initiates when FGF binds to its cognate receptor, a transmembrane tyrosine kinase receptor known as FGFR (Fibroblast Growth Factor Receptor). This binding triggers a conformational change in the receptor, leading to its dimerization and autophosphorylation of tyrosine residues within its intracellular domain.

2. **Signal Transduction:** The phosphorylated FGFR serves as a docking site for various signaling proteins, including adaptor proteins, phosphatases, and kinases. These proteins assemble into signaling complexes, initiating a cascade of downstream signaling events.

3. **Activation of Ras-MAPK and PI3K-Akt Pathways:** The primary signaling pathways activated by FGFR are the Ras-mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol 3-kinase (PI3K)-Akt pathway. These pathways are intertwined and crucial for regulating cell migration and survival.

- **Ras-MAPK Pathway:** The Ras-MAPK pathway is activated by the recruitment of the adaptor protein Grb2 to the phosphorylated FGFR. Grb2 binds to Sos, a guanine nucleotide exchange factor (GEF), which in turn activates Ras, a small GTPase. Activated Ras then activates a cascade of kinases, including Raf, MEK, and ERK. ERK eventually translocates to the nucleus, where it phosphorylates transcription factors to regulate gene expression associated with cell proliferation and survival.

- **PI3K-Akt Pathway:** The PI3K-Akt pathway is activated by the recruitment of the adaptor protein Gab1 to the phosphorylated FGFR. Gab1 activates PI3K, which phosphorylates phosphatidylinositol (PIP2) to generate PIP3. PIP3 serves as a docking site for Akt, a serine/threonine kinase. Akt is then phosphorylated and activated by PDK1 and mTORC2. Activated Akt promotes cell survival and migration by inhibiting apoptosis and stimulating the production of pro-migratory factors.

4. **Regulation of Chemotactic Signaling:** The Ras-MAPK and PI3K-Akt pathways converge to regulate the expression and activity of key proteins involved in chemotaxis.

- **Cytoskeletal Remodeling:** The activation of the Ras-MAPK pathway leads to the phosphorylation and activation of proteins involved in actin polymerization, such as cofilin and LIM kinase. This promotes the formation of lamellipodia and filopodia, crucial for cell movement.

- **Integrin Activation:** The PI3K-Akt pathway activates integrins, transmembrane receptors that mediate cell adhesion to the extracellular matrix. This adhesion provides traction for cell movement and allows the cell to sense directional cues from the environment.

- **Guidance Cues:** The FGF gradient itself acts as a chemotactic cue, guiding endothelial cell migration towards higher concentrations of FGF. Other guidance cues, such as chemokines and growth factors, can also influence the direction of cell migration.

5. **Cell Migration and Angiogenesis:** Through the intricate interplay of these signaling pathways, FGF regulates endothelial cell chemotaxis, driving their migration toward areas of tissue injury or growth. This process is essential for angiogenesis, the formation of new blood vessels, which is required for tissue repair, development, and tumor growth.

In conclusion, endothelial cell chemotaxis to fibroblast growth factor is a finely regulated process involving multiple signaling pathways and intricate protein interactions. This process is fundamental to angiogenesis and plays a critical role in various physiological and pathological processes.'
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Proteins (3)

Compounds (4)