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Koh, Young Jun,Koh, Bong Ihn,Kim, Honsoul,Joo, Hyung Joon,Jin, Ho Kyoung,Jeon, Jongwook,Choi, Chulhee,Lee, Dong Hun,Chung, Jin Ho,Cho, Chung-Hyun,Park, Won Seok,Ryu, Ji-Kan,Suh, Jun Kyu,Koh, Gou Young Ovid Technologies Wolters Kluwer -American Heart A 2011 Arteriosclerosis, thrombosis, and vascular biology Vol.31 No.5
Structural-Functional Relationship of Angiopoietin
Koh, Gou Young 이화여자대학교 세포신호전달연구센터 2003 고사리 세포신호전달 심포지움 Vol. No.5
Angiopoietin-1(Ang1) is a specific and critical growth factor for blood vessel formation. Recent studies indicated that Ang1 could be used for preventing vascular leakages, therapeutic vasculogenesis, and therapeutic endothelial cell survival. However, Ang1 protein is not easily available because generation of recombinant Ang1 is extremely difficult with current techniques. Ang1 contains 498 amino acids, including an amino-terminal secretory signal sequence. There are two cysteines and two coiled-coil domains in amino-terminal region, which could be responsible for ligand multimerization. The carboxy-terminal region of Ang1 has strong similarity with the carboxy-terminal domain of fibrinogen, which is responsible for receptor binding. Ang1 is present as higher-order multimers, could be resulted from holding together by disulfide crosslinks and coiled-coil structures. Because Ang1 has such a biochemical and biophysical characteristics, it is not soluble, aggregates easily, and sticks to everything during its generation and purification. To determine a role of amino-terminal region, truncated Ang1 that contains only fibrinogen-like domain(Ang1/FD) was generated. To determine a role of Cys^(41), Cys^(54) and Cys^(265) for Ang1 multimerization, amino acids 17-80 region was deleted(Ang1-D1) and Cys^(265) was substituted with Ser^(265)(nAng1S265). To determine a role of coiled-coil domains for Ang1 multimerization, we gradually deleted amino-terminal portion of Ang1. To generate designed multimeric Ang1, amino-terminal portion of Ang1 was replaced dimeric, trimeric, or pentameic coiled-coil domain. Our current results suggest that multimerization of Ang1 is essential not only for binding but also for activation of its receptor, Tie2.
Koh, Gou Young,ECRG members 이화여자대학교 세포신호전달연구센터 2008 고사리 세포신호전달 심포지움 Vol. No.10
VEGF-A is a prime responsible molecule for inducing tumor angiogenesis and metastasis. In comparison, angiopoietin is a supportive molecule in VEGF-A-induced tumor angiogenesis and metastasis. Therefore, double blockades of VEGF-A and angiopoietin could effectively to inhibit tumor angiogenesis, progression and metastasis. Here we designed novel molecule that can simultaneously block VEGF-A and angiopoietin by combination of minimal binding portion of VEGF-A in VEGFR1 and minimal binding portion of Ang2 in Tie2, and by connection with Fc portion of antibody IgG. We called this molecule as "double anti-angiogenic protein(DAAP)". Backbone of DAAP is structurally and functionally stable and effective for synchronous binding of VEGF-A and angiopoietin. DAAP is a highly effective molecule to reduce pathologic angiogenesis with having relatively high bioavailability, and can be potential therapeutic protein for blocking tumor and ocular angiogenesis. Molecular and cellular mechanisms for antigen clearance from dermal tissue to draining lymph node(DLN) through peripheral lymphatic vessels are not well established. To investigate role of VEGF ligands on antigen clearance, we made a local dermal tissue inflammation mouse model by introduction of LPS from Gram- bacteria and LTA from Gram+ bacteria to ear skin of mouse. This model displayed profound lymphangiogenesis, marked infiltration of CD11b+ macrophages and increased antigen clearance in the local dermal tissue and its DLN. Depletion of CD11b+ macrophage by clodronate liposome and blockade of VEGF-A or VEGF-C by VEGF-Trap and sVEGFR3 substantially reduced LPS- and LTA-induced lymphangiogenesis, CD11b+ macrophage infiltration and antigen clearance, and local lymphatic flow in the local dermal tissue and its DLN. Taken together, we concluded that VEGF ligands derived from CD11b+ macrophages are critical for antigen clearance in the dermal tissue.