Expression of the AT2 receptor developmentally programs extracellular signal-regulated kinase activity and influences fetal vascular growth

Akishita, Masahiro; Ito, Masaaki; Lehtonen, Jukka; Daviet, Laurent; Dzau, Victor J.; Horiuchi, Masatsugu

doi:10.1172/jci5182

Cited by 94 publications

(85 citation statements)

References 46 publications

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“…Positive clones resistant to G418 (800 g/ml) were analyzed by immunoblotting using anti-ATIP polyclonal antibodies. AT2 receptor binding sites were analyzed by radioligand binding performed on whole cells (8 ϫ 10 4 cells/well in 24-well dishes) using 0.25 nM [ 125 I-Sar,Ile]Ang II (PerkinElmer Life Sciences) in the presence or absence of Ang II (1 M) or CGP 42112 (1 M), as described (25). All clones were used at passages 5 to 20.…”

Section: Methodsmentioning

confidence: 99%

“…COShAT2 cells permanently expressing the human AT2 receptor have been previously described (26) and were used at passages 3 to 16. Adult rat VSMC were previously shown to express both AT1 and AT2 receptors (25). These cells were prepared as described (25) and used at passages 2 to 8.…”

Section: Methodsmentioning

confidence: 99%

“…Adult rat VSMC were previously shown to express both AT1 and AT2 receptors (25). These cells were prepared as described (25) and used at passages 2 to 8.…”

Section: Methodsmentioning

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

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172

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: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

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

Nouet

Amzallag

et al. 2004

Journal of Biological Chemistry

Self Cite

172

189

View full text Add to dashboard Cite

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“…9,14 -19 Furthermore, the AT2 receptor is highly expressed in developing organs and is postulated to be involved in tissue growth and cell differentiation. 20,21 Recent studies indicate that vascular endothelial growth factor (VEGF) may be the major mediator of the angiogenic effects of ANG II. 9,11 VEGF is a ligand for the receptor tyrosine kinase (RTK) receptors, Flt-1 (VEGF-R1) and Flk-1 (VEGF-R2), and is a potent permeability and angiogenic factor.…”

mentioning

confidence: 99%

Retinal Angiogenesis Is Mediated by an Interaction between the Angiotensin Type 2 Receptor, VEGF, and Angiopoietin

Sarlos

Rizkalla

Moravski

et al. 2003

The American Journal of Pathology

131

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There is evidence that angiotensin II, vascular endothelial growth factor (VEGF), angiopoietins, and their cognate receptors participate in retinal angiogenesis. We investigated whether angiotensin type 2-receptor blockade (AT2-RB) reduces retinal angiogenesis and alters the expression of VEGF/VEGF-R2 and angiopoietin-Tie2. Retinopathy of prematurity (ROP) was induced in Sprague Dawley (SD) rats by exposure to 80% oxygen from postnatal (P) days 0 to 11, followed by 7 days in room air. ROP shams were in room air from P0 -18. A group of ROP rats received the AT2-RB, PD123319, by mini-osmotic pump (5 mg/kg/day) from P11-18 (angiogenesis period). Evaluation of the retinal status of the AT2 receptor indicated that this receptor, as assessed by real-time PCR, immunohistochemistry, and in vitro autoradiography, was present in the retina, was more abundant than the AT1 receptor in the neonatal retina, and was increased in the ROP model. AT2-RB reduced retinal angiogenesis. VEGF and VEGF-R2 mRNA were increased in ROP and localized to blood vessels, ganglion cells, and the inner nuclear layer, and were decreased by PD123319. Angiopoietin2 and Tie2, but not angiopoietin1 mRNA were increased with ROP, and angiopoietin2 was reduced with PD123319. This study has identified a potential retinoprotective role for AT2-RB possibly mediated via interactions with VEGF-and angiopoietin-dependent pathways.

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“…This model also predicts that the absolute number of active receptors (R * ) will increase as a function of receptor density. In a recent study, Akishita et al (1999) observed that the growth difference between VSMC isolated from wild-type and AT 2 À mice was maintained even in the absence of Ang II and was not affected by the AT 2 antagonist PD123319. Consistent with this observation, we demonstrate here that the AT 2 receptor inhibits proliferation of rat and Karnik, 2000) reported that overexpression of AT 2 receptor induces ligand-independent apoptosis in Chinese hamster ovary (CHO) cells and in the A7r5 smooth muscle cell line.…”

Section: Discussionmentioning

confidence: 99%

Expression of angiotensin type II receptor downregulates Cdk4 synthesis and inhibits cell-cycle progression

et al. 2003

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Accumulating evidence suggests that angiotensin II type II (AT 2 ) receptor subtype negatively regulates cell proliferation in pathophysiological conditions associated with tissue remodeling. However, the mechanisms through which AT 2 receptor achieves this effect remain poorly understood. In this study, we demonstrate that expression of AT 2 receptor inhibits the proliferation of rat fibroblasts in a ligand-independent manner. The antiproliferative action of AT 2 is dependent on the density of surface receptors. We show that AT 2 receptor expression negatively regulates G1 phase progression in both cycling cells and G0-arrested cells stimulated to re-enter the cell cycle, but has no detectable effect on apoptosis. The delay in cell-cycle progression of AT 2 -expressing cells is associated with downregulation of cyclin E expression, decreased assembly of cyclin E-Cdk2 complexes, and the resulting attenuation of Cdk2 activation. The induction of Cdk4 expression and activity is also markedly attenuated, which likely contributes to the inhibition of cyclin E expression. Ectopic expression of Cdk4 alleviates the proliferation defect of AT 2 -expressing cells. These findings suggest that the growth-inhibitory effects of the AT 2 receptor are attributable in part to its spontaneous inhibitory action on the cell cycle machinery.

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Expression of the AT2 receptor developmentally programs extracellular signal-regulated kinase activity and influences fetal vascular growth

Cited by 94 publications

References 46 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

Retinal Angiogenesis Is Mediated by an Interaction between the Angiotensin Type 2 Receptor, VEGF, and Angiopoietin

Expression of angiotensin type II receptor downregulates Cdk4 synthesis and inhibits cell-cycle progression

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