1. B16 4T1 CT26 FL 72kD Cleaved 45kD (a) (b) Supplemenatry fig. 1 Full length (FL) and cleaved DR6 expression in B16, 4T1 and CT26 cells.

2. Isotype siNC siDR6 CD3 DC CTLA-4 Supplementary fig. 2 Flow cytometry assays for CD3, CTLA-4 and DC positive cells.

3. Website:http://www.ncbi.nlm.nih.gov/homologene/?term=DR6 Conserved Domains: Conserved Domains from CDD found in protein sequences by rpsblast searching. TNFR (cd00185) Tumor necrosis factor receptor (TNFR) domain; TNFR (cl12111)Tumor necrosis factor receptor (TNFR) domain; DD (cl14633): Death Domain Superfamily of protein-protein interaction domains. Supplementary fig. 3 Alignment of DR6 protein sequence in Euteleostomi.

4. 0.02% BSA DR6 Ab PBS 0 h 10 h Supplementary fig. 4 The chicken chorioallantoic membrane model (CAM) assays.

5. PBSDR6 Ab 24 h 0.02% BSA Supplementary fig. 5 The observation of chicken embryos size.

6. (a) PDGFR- α VEGF-D IL-6 (20ng/mL ) IL-6 (40ng/mL ) 0h 20h 48h 0h 20h 48h GAPDH (b) Supplementary fig. 6 IL-6 up-regulates the vascular formation related in B16 cells.

7. (a) Supplementary fig. 7 BAY inhibits the expression of IL-6 and the angiogenesis related protein. Con BAY VEGF-D PDGFR- α GAPDH (c) (b) (d)

8. p-P38 GAPDH IL-6 (40ng/mL) 0h 5min 30min 1h 6h P38 p-STAT3 STAT3 0h 5min 30min 1h 6h 12h GAPDH IL-6 (40ng/mL) Supplementary fig. 8 IL-6 activates P38 and STAT3. (a) (b)

9. PBS IL-6 DR6 Ab IL-6+DR6 Ab Supplementary fig. 9 IL-6 involves in the DR6-related angiogenesis.

10. Vector DR6 +/+ TRAIL VEGF-A VEGF-B VEGF-D GAPDH HEK 293T DR6 Supplementary fig. 10 The expression of VEGF-A, VEGF-B, VEGF-D in DR6 overexpressed HEK293T cells.