Fibroblast Growth Factor Receptor-1 Signaling in Pancreatic Islet β-Cells Is Modulated by the Extracellular Matrix

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Abstract
Maintenance of pancreatic β-cell mass depends on extracellular stimuli that promote survival and proliferation. In the islet, these stimuli come from the β-cell microenvironment and include extracellular matrix deposited by associated vascular endothelial cells. Fibroblast growth factor receptor-1 (FGFR1) has recently been implicated as a signaling pathway that is important for normal β-cell function. We would like to understand how extracellular matrix and FGFR1 signaling interact to promote β-cell survival and proliferation. To examine β-cell-specific receptor responses, we created lentiviral vectors with rat insulin promoter-driven expression of Venus fluorescent protein-tagged full-length (R1βv) and kinase-deficient (KDR1βv) FGFR1. Significant FGF-1-dependent activation of ERK1/2 was observed in βTC3 cells, dispersed β-cells, and β-cells in intact islets. This response was enhanced by R1βv expression and reduced by KDR1βv expression. Plating-dispersed β-cells on collagen type IV resulted in enhanced expression of endogenous FGFR1 that was associated with sustained activation of ERK1/2. Conversely, plating cells on laminin reduced expression of FGFR1, and this reduction was associated with transient activation of ERK1/2. Addition of neutralizing antibodies to inhibit β-cell attachment to laminin via α6-integrin increased high-affinity FGF-1-binding at the plasma membrane and resulted in sustained ERK1/2 activity similar to cells plated on collagen type IV. These data show that the FGF-stimulated β-cell response is negatively affected by α6-integrin binding to laminin and suggest regulation associated with vascular endothelial cell remodeling.