Maintenance of pancreatic -cell mass depends on extracellular stimuli that promote survival and proliferation. In the islet, these stimuli come from the -cell microenvironment and include extracellular matrix (ECM) 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 -cell function. We would like to understand how ECM- and FGFR1-signaling interact to promote -cell survival and proliferation. To examine -cell-specific receptor responses, we created lentiviral vectors with rat insulin promoter-driven expression of Venus fluorescent protein-tagged full-length (R1v) and kinase-deficient (KDR1v) FGFR1. Significant FGF-1-dependent activation of ERK1/2 was observed in TC3 cells, dispersed -cells and -cells in intact islets. This response was enhanced by R1v expression and reduced by KDR1v expression. Plating dispersed -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 -cell attachment to laminin via ₆-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 -cell response is negatively affected by ₆-integrin binding to laminin, and suggest regulation associated with vascular endothelial cell remodeling.