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Exploration of the Regulation of Breast Cancer by the Angiotensin II Receptor AT2

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Annual rept. 1 May 2001-30 Apr 2002

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The Angiotensin II Ang II receptor subtype AT2 is a protein with seven transmembrane domains. It was shown that the third Intracellular Loop 3rd ICL of this receptor is needed for the induction of apoptosis in some cell lines. Our recent studies suggest that the 3rd ICL of the AT2 is also involved in reducing cGMP levels in oocytes and this effect is mediated through squestering Gi alpha and possible activation of Gi beta- gamma subunits. Thus the 3 ICL of the AT2 plays a crucial role in the functions of this receptor. To further characterize signaling by the AT2, we had used yeast two-hybrid assay to identify the proteins that may directly interact with the AT2. These studies lead to the identification of a direct protein-protein interaction between the ATP binding domain of the ErbB2 and ErbB3 receptors and the AT2. A chimeric receptor in which the 3rd ICL of the AT2 was replaced with that of the AT1, and a truncated AT2 receptor that did not have the C-terminal cytoplasmic domain were unable to interact with the ATP binding domain of the human ErbB3 receptor. Moreover deleting the C-terminus of the AT2 also abolished the interaction between the AT2 and the ErbB3. Therefore the 3rd ICL and C-terminal cytoplasmic domain of the AT2 are essential for this interaction. The receptors of the ErbB family, particularly ErbB2 and ErbB3 are overexpressed and constitutively phosphorylated in many breast cancer cells and such overexpression suggests poor prognosis. Since the 3rd ICL of the AT2 is involved in growth regulation and this region is needed for the interaction between the AT2 and the human ErbB3, we hypothesized that this interaction may result in growth regulation of the breast cancer cells that overexpress ErbB2 and ErbB3.

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  • Anatomy and Physiology
  • Medicine and Medical Research

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