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Dr. Bill Barton and his PhD student Tom Seegar discovered a new mechanistic role of Tie1 in angiogenesis suggesting a potential new therapeutic target for solid-tumor cancers published in March 2010 in Molecular Cell
In order for solid tumors to get the necessary nutrients and oxygen to grow, they need to induce the formation of new blood vessels, a process called angiogenesis. Therefore, there is intense interest in determining the molecular mechanisms of angiogenesis, with the hopes of finding viable drug targets. Indeed, several drugs inhibiting angiogenesis are already in the clinic.
Reporting in the March 2010 issue of Molecular Cell, Dr. Bill Barton and colleagues add another target to the list: Tie1. Moreover, their data suggest that Tie1 is “an alternative therapeutic target [that] may be more viable than those tested in the past,” according to Dr. Barton, associate professor in the Department of Biochemistry & Molecular Biology and the Massey Cancer Center.
In this work, they resolved a long-standing conundrum in the angiogenesis field. It is known that the angiopoietin 1 & 2 (Ang1 & 2) can bind and activate Tie2, a receptor tyrosine kinase, leading to stable vessels. However, in some cells, Ang2 appears to be an antagonist of Ang1, inducing regression or sprouting of vessels. In an elegant series of experiments Dr. Barton et al. demonstrate that the key difference is Tie1 expression. Using a powerful live cell spatial proximity assay based on the FRET technique, graduate student Tom Seegar demonstrated that Tie1 is an inhibitory co-receptor of Tie2. When Tie1 is absent, both Ang1 and Ang2 activate the receptor. However, when Tie1 & 2 are expressed together, the two proteins form a heterodimer. Ang1 shifts the equilibrium towards a Tie2 homodimer and initiates signaling. In contrast, Ang2 stabilizes the heterodimer, but does not initiate signaling, thus acting as an antagonist of Ang1. Using molecular modeling-based, site-directed mutagenesis, the precise surface regions that mediate the Tie1-Tie2 interactions were mapped.
Together, these results suggest that dynamic interactions between Tie1 & 2 control Tie2 activation, and therefore vascular homeostasis. The exquisite level of molecular control indicates the importance of restricting Tie2 activation to prevent pathological angiogenesis. The Tie1-Tie2 interface, mapped at the molecular level, can now serve as an attractive therapeutic target for the rational development of drugs to inhibit their interaction.
