The mitogenic activity of fibroblast growth factor-1 correlates with its internalization and limited proteolytic processing.
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.
Grieb
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TA
Department of Tissue Biology, Holland Laboratory, American Red Cross, Rockville, Maryland, USA.
Burgess
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WH
D016475:3T3 Cells / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D002467:Cell Nucleus / Q000737:chemistry; D002746:Chlorpromazine / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003593:Cytoplasm / Q000737:chemistry; D003600:Cytosol / Q000737:chemistry; D018492:Dopamine Antagonists / Q000494:pharmacology; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology*; D016220:Fibroblast Growth Factor 1; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism* / Q000494:pharmacology; D005372:Filipin / Q000494:pharmacology; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D008934:Mitogens / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D000998:Antiviral Agents; D015853:Cysteine Proteinase Inhibitors; D018492:Dopamine Antagonists; D007976:Leupeptins; D008024:Ligands; D008934:Mitogens; D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1; D005372:Filipin; C032854:leupeptin; D002746:Chlorpromazine