Negative regulation of mitogenic pathways is a fundamental process that remains poorly characterized. The angiotensin II AT2 receptor is a rare example of a 7-transmembrane domain receptor that negatively cross-talks with receptor tyrosine kinases to inhibit cell growth. In the present study, we report the molecular cloning of a novel protein, ATIP1 (AT2-interacting protein), which interacts with the C-terminal tail of the AT2 receptor, but not with those of other receptors such as angiotensin AT1, bradykinin BK2, and adrenergic ␤ 2 receptor. ATIP1 defines a family of at least four members that possess the same domain of interaction with the AT2 receptor, contain a large coiled-coil region, and are able to dimerize. Ectopic expression of ATIP1 in eukaryotic cells leads to inhibition of insulin, basic fibroblast growth factor, and epidermal growth factor-induced ERK2 activation and DNA synthesis, and attenuates insulin receptor autophosphorylation, in the same way as the AT2 receptor. The inhibitory effect of ATIP1 requires expression, but not ligand activation, of the AT2 receptor and is further increased in the presence of Ang II, indicating that ATIP1 cooperates with AT2 to transinactivate receptor tyrosine kinases. Our findings therefore identify ATIP1 as a novel early component of growth inhibitory signaling cascade.The potent vasoactive peptide angiotensin II (Ang II) 1 is also an important regulator of cellular proliferation and hypertrophy. This peptide binds to two main subtypes of receptors (AT1 and AT2) that both belong to the superfamily of G proteincoupled receptors (GPCR) but display opposite biological and physiological effects. The AT1 receptor mediates most of the known cardiovascular and central actions of Ang II. This subtype has mitogenic and trophic effects in many tissues and cell types and transduces multiple intracellular signaling cascades typically associated with GPCR activation. In contrast, AT2 behaves like a "natural antagonist" of the AT1 subtype on most physiological functions, and induces anti-proliferative and proapoptotic effects in vitro and in vivo (for reviews, see Refs. 1-5).The AT2 receptor activates unconventional signaling pathways that in most cases do not involve coupling to classical regulatory G proteins. A growing body of evidence indicates that anti-growth effects of the AT2 receptor are associated with activation of tyrosine phosphatases and inhibition of protein kinases, which ultimately lead to inhibition of extracellular regulated kinase (ERK2). In many cell types, AT2 is functionally coupled to the Src homology 2 domain-containing tyrosine phosphatase SHP-1 (6 -8). This phosphatase has been shown to play a central role in the AT2 signaling cascades leading to inhibition of AT1-induced PYK2 and Jun kinase (9), AT1-transactivated EGF receptor tyrosine kinase (10), and insulin-induced phosphatidylinositol 3-kinase and Akt activation (11).AT2 negatively cross-talks with receptor tyrosine kinases (RTK) such as bFGF, EGF, and insulin receptors (10, 12, 13) by targeti...

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