Role of C‐terminal cytoplasmic domain of the AT2 receptor in ligand binding and signaling

Pulakat, Lakshmi; Gray, A.W.; Johnson, Janean; Knowle, Dieter; Burns, Veronica Elizabeth; Gavini, Nara

doi:10.1016/s0014-5793(02)03005-3

Cited by 20 publications

(21 citation statements)

References 49 publications

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“…This was suggested by the observation that ATIP1 and AT2 attenuate RTK autophosphorylation, and by recent studies showing that ErbB3, a member of the EGF receptor family, interacts with the AT2 receptor C-terminal portion (20,21). Experiments performed on transfected CHO-hAT2 and COS-AT2 cells failed, however, to detect direct interaction between ATIP1 and the EGF receptor or the insulin receptor ␤-chain, either at basal levels or after stimulation with Ang II, EGF, or insulin (data not shown).…”

Section: Discussionmentioning

confidence: 96%

“…ATRAP is one such example of a novel protein that selectively interacts with the AT1 receptor C terminus and down-regulates its activity (18,19). Regarding the AT2 receptor, recent studies have documented a direct interaction of its C-terminal tail with ErbB3, a member of the EGF receptor family (20,21), and with the transcription factor promyelocytic zinc finger containing protein (PLZF) abundantly expressed in the heart (22).…”

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confidence: 99%

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Trans-inactivation of Receptor Tyrosine Kinases by Novel Angiotensin II AT2 Receptor-interacting Protein, ATIP

Nouet

Amzallag

et al. 2004

Journal of Biological Chemistry

173

189

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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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Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 99%

Trans-inactivation of Receptor Tyrosine Kinases by Novel Angiotensin II AT2 Receptor-interacting Protein, ATIP

Nouet

Amzallag

et al. 2004

Journal of Biological Chemistry

173

189

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“…The currents generated by cloned AT1 and AT2 expressed in the oocytes are similarly mediated by gating of those chloride channels. These results were somewhat unexpected because the rAT2 receptors are known to reduce the intracellular levels of cGMP [29]. Nonetheless, in Xenopus oocytes the cloned receptor coupled to the DAG/IP 3 pathway and generated the characteristic oscillatory currents.…”

Section: Discussionmentioning

confidence: 98%

Mammalian AT2 Receptors Expressed in <i>Xenopus laevis</i> Oocytes Couple to Endogenous Chloride Channels and Stimulate Germinal Vesicle Break Down

Reyes

Pulakat

Miledi

et al. 2009

Cell Physiol Biochem

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Background and aims: A comparative analysis was performed of the properties of cloned AT1 and AT2 receptors and their ability to induce ion currents and oocyte maturation. Methods: Frog oocytes were injected with cRNA that codes for rat AT1A and AT2 and bovine AT1 receptors and membrane currents were recorded by using the two-microelectrode voltage-clamp technique. Oocyte maturation was scored by observation of the germinal vesicle breakdown (GVBD). Results: Xenopus oocytes expressing AT1 or AT2 generated oscillatory chloride currents by coupling to the diacylglycerol/inositol-3-phosphate (DAG/IP₃) cascade. Ang II activation of collagenase-defolliculated oocytes expressing rat AT1A yielded larger chloride currents (9.2±3.4 A) than those generated by oocytes expressing bovine AT1 (3.78±2.6 A). Oocytes expressing rat AT1A were recovered from desensitization after 0.5 h and completely after 10.5 h; whereas oocytes expressing bovine AT1 receptors were unable to do so. Expression of rat AT2 generated smaller chloride currents (32-210 nA). Expression of AT2 receptors triggered GVBD whereas AT1 did not. The proportion of oocytes developing GVBD was greater for folliculated oocytes than for oocytes that were defolliculated. Furthermore, oocytes injected with AT2 secreted into the media, a heat-resistant factor(s) that stimulated GVBD of oocytes. This media elicited inward and outward membrane currents when applied to non-injected oocytes. Conclusion: Activation of AT1 and AT2 receptors couple to similar metabolic cascades in Xenopus laevis oocytes. However, the pathway activated by AT2 diverges to induce oocyte maturation.

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“…On the other hand, recent experimental studies have shown the existence of proteins interacting with Ang II receptors, screened by the yeast-based two-hybrid protein-protein interaction assay technique, and have also revealed their functions. [5][6][7][8][9][10][11][12] For the AT 1 receptor, AT 1 receptor-associated protein could act as a negative regulator in AT 1 receptor-mediated cell proliferation and vascular remodeling, at least in part by the enhancement of AT 1 receptor internalization. 13,14 On the other hand, the AT 2 receptor-interacting protein seems to act as a novel early component of the growth inhibitory signaling cascade of the AT 2 receptor.…”

Section: New Paradigm Shift Of Renin-angiotensin Systemmentioning

confidence: 99%

Inhibition of the renin–angiotensin system and target organ protection

et al. 2009

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The renin-angiotensin system (RAS) is involved in the pathological mechanisms of target organ damage, as well as in the induction of hypertension. RAS inhibition by angiotensin converting enzyme (ACE) inhibitors and angiotensin (Ang) II receptor blockers can prevent tissue damage by inhibition of Ang II type 1 receptor signaling. A beneficial effect of RAS inhibition on the heart, vasculature and kidney in cardiovascular disease has been reported. However, RAS inhibition can also prevent fibroproliferative diseases and damage of other tissues, such as brain, adipose tissue and muscle, because local RAS has an important role in tissue damage compared with circulating RAS. Moreover, other players, such as Ang II type 2 receptor signaling, aldosterone and ACE2 have been highlighted. Furthermore, there has also been a focus on the emerging concept of regulation of RAS, such as receptor-interacting proteins and receptor modifications, in the new discovery of therapeutic agents for tissue protection. The RAS has a pivotal role in various target organ damage, with complicated mechanisms; therefore, blockade of RAS may be therapeutically effective in preventing organ damage, as well as in having an antihypertensive effect.

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Role of C‐terminal cytoplasmic domain of the AT2 receptor in ligand binding and signaling

Cited by 20 publications

References 49 publications

Trans-inactivation of Receptor Tyrosine Kinases by Novel Angiotensin II AT2 Receptor-interacting Protein, ATIP

Trans-inactivation of Receptor Tyrosine Kinases by Novel Angiotensin II AT2 Receptor-interacting Protein, ATIP

Mammalian AT2 Receptors Expressed in <i>Xenopus laevis</i> Oocytes Couple to Endogenous Chloride Channels and Stimulate Germinal Vesicle Break Down

Inhibition of the renin–angiotensin system and target organ protection

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