CD146 is a coreceptor for VEGFR-2 in tumor angiogenesis.
CD146 is a novel endothelial biomarker and plays an essential role in angiogenesis; however, its role in the molecular mechanism underlying angiogenesis remains poorly understood. In the present study, we show that CD146 interacts directly with VEGFR-2 on endothelial cells and at the molecular level and identify the structural basis of CD146 binding to VEGFR-2. In addition, we show that CD146 is required in VEGF-induced VEGFR-2 phosphorylation, AKT/p38 MAPKs/NF-κB activation, and thus promotion of endothelial cell migration and microvascular formation. Furthermore, we show that anti-CD146 AA98 or CD146 siRNA abrogates all VEGFR-2 activation induced by VEGF. An in vivo angiogenesis assay showed that VEGF-promoted microvascular formation was impaired in the endothelial conditional knockout of CD146 (CD146(EC-KO)). Our animal experiments demonstrated that anti-CD146 (AA98) and anti-VEGF (bevacizumab) have an additive inhibitory effect on xenografted human pancreatic and melanoma tumors. The results of the present study suggest that CD146 is a new coreceptor for VEGFR-2 and is therefore a promising target for blocking tumor-related angiogenesis.
Key Laboratory of Protein and Peptide Pharmaceutical, National Laboratory of Biomacromolecules, Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Tianxia
T
Jiang
Jie
J
Zhuang
Hongxia
H
Duan
Yongting
Y
Luo
Qiqun
Q
Zeng
Kelong
K
Fan
Huiwen
H
Yan
Di
D
Lu
Zhongde
Z
Ye
Junfeng
J
Hao
Jing
J
Feng
Dongling
D
Yang
Xiyun
X
Yan
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D051929:CD146 Antigen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000970:Antineoplastic Agents; D051929:CD146 Antigen; C497902:MCAM protein, human; C497903:Mcam protein, mouse; D050505:Mutant Proteins; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D040301:Vascular Endothelial Growth Factor Receptor-2