Figure 1.

Mechanisms whereby VEGFR2 and S1PR1 promote tumor growth. VEGF/VEGFR2 and S1P/S1PR1 signaling synergistically regulates endothelial migration and thereby tumor angiogenesis. S1P generated from cancer cells ligates S1PR1 in S1PR1 + ECs, stimulates Gi, which in turn promotes c-Abl1 activity by VEGF leading to the VEGFR2 phosphorylation at Y951 results in persistent activation of VEGFR2 on EC plasmalemma. The relentless synergistic activity of VEGFR2 and S1PR1 in ECs prolongs Rac1 activity in a Tiam1 dependent manner leading to the establishment of tumor vasculature and have an advantage for recurrence of aggressive refractory tumor after anti-VEGFR2 therapy. While, in ECs lacking S1PR1, VEGF activated VEGFR2 pursues canonical phosphorylation at Y1175 followed by receptor internalization to activate ERK1/2/3 leading to impaired EC migration and tumor vascularization.