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The mitogenic activity of fibroblast growth factor-1 correlates with its internalization and limited proteolytic
1Department of Tissue Biology, Holland Laboratory, American Red Cross, Rockville, Maryland, USA.
Abstract:
The fibroblast growth factor-1 (FGF-1) mitogenic signal transduction pathway is not well characterized, and evidence indicates that FGF-1 binding to and activation of cell-surface receptors is not solely sufficient for a full mitogenic response. Although initiation of the phosphorylation signaling cascades are likely important in FGF-1-induced mitogenic signaling, there appear to be additional signaling requirements. In this study, we demonstrate that FGF-1 internalization and subsequent processing correlates with the mitogenic potential of the growth factor on NIH 3T3 cells. Using site-directed mutants of FGF-1 and inhibitors of the endocytic and degradative pathways, we provide evidence for growth factor internalization and exposure to an acidic environment as necessary components of FGF-1-induced mitogenesis. In addition, a protease-sensitive event(s) appears critical for a complete mitogenic response to FGF-1, whereas, this protease sensitivity was not detected under the same conditions for serum-stimulated mitogenesis. Therefore, proteolytic modification of internalized FGF-1 may result in the activation of additional, intracellular signaling events.
Insights
Fibroblast growth factor-1 (FGF-1) requires internalization and processing for its full mitogenic effect. Proteolytic modification of internalized FGF-1 activates crucial intracellular signaling pathways for cell growth.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- The fibroblast growth factor-1 (FGF-1) signaling pathway's role in cell growth is not fully understood.
- FGF-1 receptor binding and activation alone do not fully explain its mitogenic effects.
- Additional intracellular signaling events are likely required for FGF-1-induced mitogenesis.
Purpose of the Study:
- To investigate the role of FGF-1 internalization and processing in its mitogenic signaling.
- To determine if endocytosis and exposure to acidic environments are necessary for FGF-1 activity.
- To explore the involvement of proteolytic events in FGF-1-mediated cell proliferation.
Main Methods:
- Utilized site-directed mutants of FGF-1 to assess its function.
- Employed inhibitors targeting endocytic and degradative cellular pathways.
- Compared FGF-1 signaling with serum-stimulated mitogenesis under various conditions.
Main Results:
- FGF-1 internalization and processing correlated with its mitogenic potential in NIH 3T3 cells.
- Growth factor internalization and exposure to acidic environments were essential for FGF-1-induced mitogenesis.
- A protease-sensitive event, critical for FGF-1 mitogenesis, was not observed in serum-stimulated cells.
Conclusions:
- FGF-1 internalization and subsequent proteolytic modification are critical for a complete mitogenic response.
- These processes may lead to the activation of intracellular signaling events distinct from initial receptor activation.
- Understanding these mechanisms provides new insights into FGF-1 signal transduction and cell growth regulation.