Anthrax toxin receptor 1(ANTXR1),also known as tumor endothelial marker 8,is a highly conserved cell surface protein overexpressed in tumor-infiltrating vessels.It was first found in vascular endothelial cells of huma...Anthrax toxin receptor 1(ANTXR1),also known as tumor endothelial marker 8,is a highly conserved cell surface protein overexpressed in tumor-infiltrating vessels.It was first found in vascular endothelial cells of human colorectal cancer.Although our understanding of its physiological function is limited,it has been found that ANTXR1 binds collagen and promotes migration of endothelial cells in vitro.ANTXR1 is upregulated in vessels of different tumor types in mice and humans,and is also expressed by tumor cells themselves in some tumors,such as gastric,lung,intestinal and breast cancer.Developmental angiogenesis and wound healing were not disturbed in ANTXR1 knockout mice,but compared with wild-type mice,growth of melanoma was impaired after ANTXR1 knockout,indicating that host-derived ANTXR1 can promote tumor growth on the basis of immune activity.Previous studies have shown that ANTXR1 vaccines or sublethal doses of anthrax toxin can inhibit angiogenesis,slow tumor growth and prolong survival.These studies suggest that ANTXR1 is necessary for tumor rather than physiological angiogenesis.It has been found that ANTXR1 plays an important role in tumor angiogenesisas well as in the growth and metastasis of many kinds of tumors.This article reviews the physiological function of ANTXR1 and its role in different kinds of cancer.展开更多
LRP6,a co-receptor for the morphogen Wnt,aids endocytosis of anthrax complexes.Here we report that Dickkopf1(DKK1)protein,a secreted LRP6 ligand and antagonist,is also a modulator of anthrax toxin sensitivity.shRNA-me...LRP6,a co-receptor for the morphogen Wnt,aids endocytosis of anthrax complexes.Here we report that Dickkopf1(DKK1)protein,a secreted LRP6 ligand and antagonist,is also a modulator of anthrax toxin sensitivity.shRNA-mediated gene silencing or TALEN-mediated gene knockout of DKK1 reduced sensitivity of cells to PA-dependent hybrid toxins.However,unlike the solely inhibitory effect on Wnt signaling,the effects of DKK1 overexpression on anthrax toxicity were bidirectional,depending on its endogenous expression and cell context.Fluorescence microscopy and biochemical analyses showed that DKK1 facilitates internalization of anthrax toxins and their receptors,an event mediated by DKK1-LRP6-Kremen2 complex.Monoclonal antibodies against DKK1 provided dose-dependent protection to macrophages from killing by anthrax lethal toxin(LT).Our discovery that DKK1 forms ternary structure with LRP6 and Kremen2 in promoting PA-mediated toxin internalization provides a paradigm for bacterial exploitation of mechanisms that host cells use to internalize signaling proteins.展开更多
基金Supported by the National Natural Science Foundation of China,No.81472714the Central Plains Thousand Talents Plan-Central Plains Leading Talent Project,No.204200510023。
文摘Anthrax toxin receptor 1(ANTXR1),also known as tumor endothelial marker 8,is a highly conserved cell surface protein overexpressed in tumor-infiltrating vessels.It was first found in vascular endothelial cells of human colorectal cancer.Although our understanding of its physiological function is limited,it has been found that ANTXR1 binds collagen and promotes migration of endothelial cells in vitro.ANTXR1 is upregulated in vessels of different tumor types in mice and humans,and is also expressed by tumor cells themselves in some tumors,such as gastric,lung,intestinal and breast cancer.Developmental angiogenesis and wound healing were not disturbed in ANTXR1 knockout mice,but compared with wild-type mice,growth of melanoma was impaired after ANTXR1 knockout,indicating that host-derived ANTXR1 can promote tumor growth on the basis of immune activity.Previous studies have shown that ANTXR1 vaccines or sublethal doses of anthrax toxin can inhibit angiogenesis,slow tumor growth and prolong survival.These studies suggest that ANTXR1 is necessary for tumor rather than physiological angiogenesis.It has been found that ANTXR1 plays an important role in tumor angiogenesisas well as in the growth and metastasis of many kinds of tumors.This article reviews the physiological function of ANTXR1 and its role in different kinds of cancer.
基金supported in part by the National Natural Science Foundation of China(30770465,31070115)the National Basic Research Program of China(2010CB911800)+1 种基金the Peking-Tsinghua Center for Life Sciences(to WenSheng Wei)by an award(HDTRA1-06-C-0039)from the US Defense Threat Reduction Agency(to Stanley N.Cohen)
文摘LRP6,a co-receptor for the morphogen Wnt,aids endocytosis of anthrax complexes.Here we report that Dickkopf1(DKK1)protein,a secreted LRP6 ligand and antagonist,is also a modulator of anthrax toxin sensitivity.shRNA-mediated gene silencing or TALEN-mediated gene knockout of DKK1 reduced sensitivity of cells to PA-dependent hybrid toxins.However,unlike the solely inhibitory effect on Wnt signaling,the effects of DKK1 overexpression on anthrax toxicity were bidirectional,depending on its endogenous expression and cell context.Fluorescence microscopy and biochemical analyses showed that DKK1 facilitates internalization of anthrax toxins and their receptors,an event mediated by DKK1-LRP6-Kremen2 complex.Monoclonal antibodies against DKK1 provided dose-dependent protection to macrophages from killing by anthrax lethal toxin(LT).Our discovery that DKK1 forms ternary structure with LRP6 and Kremen2 in promoting PA-mediated toxin internalization provides a paradigm for bacterial exploitation of mechanisms that host cells use to internalize signaling proteins.
