In subconfluent endothelial cells, interaction of VEGF with its type-2 receptor (VEGFR2) activates the MAPK pathway. MAPK (ERK1/2) phosphorylates VEGFR2 as well as transcription factors that stimulate uPAR synthesis. The phosphorylated VEGFR2 induces detachment of β-catenin from nearby VE-cadherin, thus promoting cell proliferation. Therefore, sparsely seeded endothelial cells show VEGF-dependent uPAR up-regulation with a strong increase of invasion and are provided with free β-catenin available for nuclear translocation, while the density-enhanced phosphatase-1 (DEP-1) is scarcely represented. Overall, these features foster endothelial-cell migration and growth. In confluent endothelial cells VEGFR2, VE-cadherin, and overexpressed DEP-1 undergo junction clustering. The presence of overexpressed DEP-1 impairs MAPK activation, thereby inhibiting uPAR synthesis and VEGFR-2 phosphorylation. The growth-inhibitory effects are believed to be mediated by the capacity of VE-cadherin to link β-catenin at the membrane, limiting in this way its nuclear translocation. Coupling growth inhibition with low uPAR levels results in exhaustion of the angiogenesis program.