Previously we have shown that AIP1, a new member of RAS-GAP family protein, binds to ASK1 and positively regulates TNF-induced activation of the proapoptotic kinase ASK1. AIP1 is expressed on the surface of endothelial cells and is translocated to cytoplasm in response to TNF stimulation, and forms a complex containing TRADD, RIP1 and TRAF2, resulting a apoptotic signaling complex. It has also been shown that AIP1 expression was down-regulated in prostate, lung and breast cancer cell lines, indicating that AIP1 might be a tumor suppressor. In the present study, we show that AIP1 via its C2 domain binds to a potent angiogenic receptor VEGFR2 in endothelial cells. When co-transfected in 293T cells, AIP1 induces degradation of VEGFR2, resulting in reduced phopshorylation of VEGFR2. Knockdown of AIP1 in endothelial cells by siRNA of AIP1 augments VEGF-induced phosphorylation of VEGFR2 and downstream effector PLC-?. To further investigate in vivo functions of AIP1, we have generated AIP1-deficient mice by deleting the exone 5 and 6. Mouse lung endothelial cells (MLEC) isolated from AIP1−/ − mice migrate faster than those from wild-type mice. To define the role of AIP1 in tumor growth, Lewis Lung Carcinoma (LLC) were implanted subcutaneously into AIP1−/ − and AIP−/+ mice. The tumor growth in AIP−/ − is faster than AIP−/+ mice. Taken together, our data demonstrate that AIP1 is a novel angeogenic inhibitor, probably by enhancing ASK1-dependent proapoptotic signaling while suppressing VEGFR2-dependent angiogenesis.