The mitogenic activity of fibroblast growth factor-1 correlates with its internalization and limited proteolytic processing

• Published in: Journal of cellular physiology Vol. 184; no. 2; pp. 171 - 182
• Main Authors: Grieb, Teri A., Burgess, Wilson H.
• Format: Journal Article
• Language: English
• Published: New York John Wiley & Sons, Inc 01.08.2000
• Subjects: 3T3 Cells - drug effects; 3T3 Cells - metabolism; Animals; Antiviral Agents - pharmacology; Cell Nucleus - chemistry; Chlorpromazine - pharmacology; Cysteine Proteinase Inhibitors - pharmacology; Cytoplasm - chemistry; Cytosol - chemistry; Dopamine Antagonists - pharmacology; Endocytosis - drug effects; Endocytosis - physiology; Fibroblast Growth Factor 1; Fibroblast Growth Factor 2 - metabolism; Fibroblast Growth Factor 2 - pharmacology; Filipin - pharmacology; Humans; Leupeptins - pharmacology; Ligands; Mice; Mitogens - physiology; Signal Transduction - drug effects; Signal Transduction - physiology
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/1097-4652(200008)184:2<171::AID-JCP4>3.0.CO;2-J

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. J. Cell. Physiol. 184:171–182, 2000. © 2000 Wiley‐Liss, Inc.