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 pathwa y is not well characterized, and evidence indicates that FGF-1 binding to a nd activation of cell-surface receptors is not solely sufficient for a full mitogenic response. Although initiation of the phosphorylation signaling c ascades are likely important in FGF-1-induced mitogenic signaling, there ap pear to be additional signaling requirements. In this study, we demonstrate that FGF-1 internalization and subsequent processing correlates with the m itogenic potential of the growth factor on NIH 3T3 cells. Using site-direct ed mutants of FGF-1 and inhibitors of the endocytic and degradative pathway s, we provide evidence for growth factor internalization and exposure to an acidic environment as necessary components of FGF-1-induced mitogenesis. I n addition, a protease-sensitive event(s) appears critical for a complete m itogenic response to FGF-1, whereas, this protease sensitivity was not dete cted under the same conditions for serum-stimulated mitogenesis. Therefore, proteolytic modification of internalized FGF-1 may result in the activatio n of additional, intracellular signaling events. J. Cell. Physiol. 184:171- 182, 2000. (C) 2000 Wiley-Liss, Inc.