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Analysis of Functional Domains of Angiotensin II Type 2 Receptor Involved in Apoptosis

Division of Cardiovascular Medicine (J.Y.A.L., L.D., M.H., V.J.D.) Harvard Medical School Brigham and Women’s Hospital Boston, Massachusetts 02115
Institut Cochin de Génétique Moléculaire (C.N.) Centre Nationale de Recherche Scientifique UPR 0415 75014 Paris, France

We previously demonstrated that the intracellular third loop (i3 loop) of angiotensin II type 2 receptor (AT₂) plays a key role in mediating the biological functions of this receptor. To determine which residues are important for AT₂ signaling, mutated receptors with serial deletions within the i3 loop were stably expressed in PC12 cells. Deletion of residues 240–244 within the intermediate portion of the i3 loop resulted in a complete loss of AT₂-mediated apoptosis, inhibition of extracellular signal-regulated kinases (ERK), and SHP-1 activation. In contrast to well characterized heptahelical receptors, the AT₂ functions were not affected by deletions of the amino- or carboxyl-terminal portions of the i3 loop. Alanine substitutions further demonstrated that lysine 240, asparagine 242, and serine 243 are key residues for AT₂-induced apoptosis, ERK inhibition, and SHP-1 activation. To examine whether a functional link exists between activation of SHP-1 and apoptosis, we used a catalytically inactive SHP-1 mutant and demonstrated that preventing SHP-1 activation strongly attenuates AT₂-induced ERK inhibition and apoptosis. Our data demonstrate that the intermediate portion of the i3 loop is important for AT₂ function and that SHP-1 is a proximal effector of the AT₂ receptor that is implicated in the inhibition of ERKs and in the apoptotic effect of this receptor.

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