Abstract：
:The vascular endothelial growth factor-A (VEGF-A)-VEGFR2 pathway drives tumor vascularization by activating proangiogenic signaling in endothelial cells (ECs). Here, we show that EC-sphingosine-1-phosphate receptor 1 (S1PR1) amplifies VEGFR2-mediated angiogenic signaling to enhance tumor growth. We show that cancer cells induce S1PR1 activity in ECs, and thereby, conditional deletion of S1PR1 in ECs (EC-S1pr1-/- mice) impairs tumor vascularization and growth. Mechanistically, we show that S1PR1 engages the heterotrimeric G-protein Gi, which amplifies VEGF-VEGFR2 signaling due to an increase in the activity of the tyrosine kinase c-Abl1. c-Abl1, by phosphorylating VEGFR2 at tyrosine-951, prolongs VEGFR2 retention on the plasmalemma to sustain Rac1 activity and EC migration. Thus, S1PR1 or VEGFR2 antagonists, alone or in combination, reverse the tumor growth in control mice to the level seen in EC-S1pr1-/- mice. Our findings suggest that blocking S1PR1 activity in ECs has the potential to suppress tumor growth by preventing amplification of VEGF-VEGFR2 signaling.
journal_name
Cell Repjournal_title
Cell reportsauthors
Balaji Ragunathrao VA,Anwar M,Akhter MZ,Chavez A,Mao Y,Natarajan V,Lakshmikanthan S,Chrzanowska-Wodnicka M,Dudek AZ,Claesson-Welsh L,Kitajewski JK,Wary KK,Malik AB,Mehta Ddoi
10.1016/j.celrep.2019.11.036subject
Has Abstractpub_date
2019-12-10 00:00:00pages
3472-3487.e4issue
11issn
2211-1247pii
S2211-1247(19)31518-9journal_volume
29pub_type
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