Angiotensin II type 2 receptors mediate inhibition of mitogen-activated protein kinase cascade and functional activation of SHP-1 tyrosine phosphatase

Bedecs, Katarina; Elbaz, Nathalie; Sutren, Malène; Masson, Maryline; Susini, Christiane; Strosberg, A. Donny; Nahmias, Clara

doi:10.1042/bj3250449

Cited by 211 publications

(173 citation statements)

References 55 publications

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“…Consistent to the previously reported observation (8), stimulation of AT 2 receptor by 0.1 M of Ang II in COS-7 cells cotransfected with HA-AT 2 and SHP-1 induced rapid SHP-1 activation as assayed in immunocomplexes prepared with anti-SHP-1 antibodies (Fig. 1A).…”

Section: Inactive Shp-1 Constitutively and Physically Associates Withsupporting

confidence: 92%

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G_βγ-independent constitutive association of G_αswith SHP-1 and angiotensin II receptor AT₂is essential in AT₂-mediated ITIM-independent activation of SHP-1

Sun

Douglas

2002

Proc. Natl. Acad. Sci. U.S.A.

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Conventional mode of activation of SH2 domain-containing phosphatase 1 (SHP-1) by a single transmembrane (TM) inhibitory receptor such as killer cell inhibitory receptor, Fc␥ receptor type IIb1, and paired Ig-like receptors of inhibitory types requires tyrosine phosphorylation of immunoreceptor tyrosine-based inhibitory (ITIM) motifs in the cytoplasmic domains of the inhibitory receptors. Contrary to this paradigm, AT 2, a G protein-coupled 7TM receptor that does not undergo tyrosine phosphorylation in response to angiotensin II (Ang II) stimulation, also activates SHP-1. Here we show that SHP-1 constitutively and physically associates with AT2 receptor in transfected COS-7 cells. On stimulation by Ang II, SHP-1 becomes activated and dissociated from AT2 receptor, independent of pertussis toxin. Cotransfection of transducin G␤␥ inhibits SHP-1͞AT2 association and the SHP-1 activation, whereas cotransfection of C-terminal of ␤-adrenergic receptor kinase, which abrogates G ␤␥ signaling, facilitates SHP-1 activation. Surprisingly, SHP-1͞AT2 association and the SHP-1 activation requires the presence of G␣s as shown by differential coimmunoprecipitation, dominant negative G␣s, constitutively active G␣s, and G␣ peptides. A mutant AT2 receptor D141A-R142L that is inactive in G␣ protein activation constitutively associates with SHP-1 and activates it. Together, these results indicate that G␣s alone, rather than exclusively in the form of G␣␤␥ heterotrimer may facilitate signal transduction for G protein-coupled receptors, suggesting a novel mechanism distinct from the classic paradigm of heterotrimeric G proteins. The AT2-mediated ITIM-independent activation of SHP-1 that is distinct from the conventional mode of activation, may represent a general paradigm for activation of SHP-1͞2-class tyrosine phosphatases by G protein-coupled receptors.GPCR ͉ signal transduction T he G protein-coupled receptors (GPCR) AT 1 and AT 2 are the two major subtypes that transduce signals for angiotensin II (Ang II), a potent vasoactive octapeptide (Asp 1 -Arg 2 -Val 3 -Tyr 4 -Ile 5 -His 6 -Pro 7 -Phe 8 ) and a growth factor. Activation of AT 1 and AT 2 receptors by Ang II results in opposing actions of stimulation and inhibition. The AT 1 -mediated stimulatory actions as well as signal transductions are well documented, whereas the AT 2 -mediated inhibitory actions and signal transductions remain poorly understood (1-4). Most recently, studies have shown that the AT 2 receptor not only couples to pertusis toxin (PTX)-sensitive G i␣2 and G i␣3 proteins (5), but also activates a SH2 domain-containing tyrosine phosphatase (SHP-1) (5-10). Deletion or alanine substitutions of residues 240-244 within the intermediate portion of the cytoloop 3 has been shown to result in a complete loss of AT 2 -mediated apoptosis, inhibition of extracellular signal-regulated kinases, and SHP-1 activation (10).SHP-1, an intracellular protein tyrosine phosphatase (PTPase) containing two SH2 domains at the N-terminal end, plays a central role in blocking cell activ...

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Section: Inactive Shp-1 Constitutively and Physically Associates Withsupporting

confidence: 92%

“…However, the AT 2 -mediated SHP-1 activation is PTX-insensitive (8). These contradictory findings do not support an involvement of G ␣i proteins in AT 2 -mediated SHP-1 activation.…”

Section: At2-mediated Shp-1 Activation Is Independent Of G Protein Acmentioning

confidence: 83%

G_βγ-independent constitutive association of G_αswith SHP-1 and angiotensin II receptor AT₂is essential in AT₂-mediated ITIM-independent activation of SHP-1

Sun

Douglas

2002

Proc. Natl. Acad. Sci. U.S.A.

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“…In quiescent N1E-115 neuroblastoma cells expressing only the AT 2 receptor, basal MAPK activity was not affected by Ang II treatment. However, Ang II prevented the fetal calf serum-as well as epidermal growth factor-induced activation of ERK1 and ERK2 (Bedecs et al 1997). Furthermore, Ang II-induced neurite outgrowth is associated with changes in the levels of microtubuleassociated proteins (MAPs), such as up-regulation of MAP2c in NG108-15 cells and MAP2 in PC12 W cells, and downregulation of MAP1B in PC12 W cells (Laflamme et al 1996;Stroth et al 1998).…”

Section: Discussionmentioning

confidence: 99%

Contribution of bradykinin and nitric oxide to AT₂ receptor‐mediated differentiation in PC12 W cells

Zhao

Biermann

Luther

et al. 2003

Journal of Neurochemistry

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We investigated the effect of angiotensin II on intracellular cyclic GMP content and neurite outgrowth as an indicator of cell differentiation in PC12 W cells. Neurite outgrowth was examined by phase-contrast microscopy. Outgrown neurites were classified as small, medium and large, and were expressed as neurites per 100 cells. Angiotensin II (10 )7 M) increased the outgrowth of medium and large neurites by mean ± SEM 20.2 ± 2.3 and 6.6 ± 1.4 compared with 1.66 ± 0.5 and 0.1 ± 0.06 neurites per 100 cells in control. Cellular cyclic GMP content increased by 50-250% with angiotensin II at concentrations of 10 )6 -10 )4 M. Both blockade of AT 2 receptors and of nitric oxide synthase markedly reduced angiotensin II-induced neurite outgrowth and cyclic GMP production. In contrast, B 2 receptor blockade had no effect or even increased these angiotensin II effects. Sodium nitroprusside and 8-bromo-cyclic GMP both mimicked the effects of angiotensin II on cell differentiation. The protein kinase G inhibitor KT-5823 inhibited the neurite outgrowth induced by both angiotensin II and 8-bromo-cyclic GMP. Our results demonstrate that angiotensin II can stimulate cell differentiation in PC12 W cells by nitric oxide-related and cyclic GMP-dependent mechanisms. The effects of angiotensin II on cell differentiation and cyclic GMP production were mediated via the AT 2 receptor and further enhanced by bradykinin B 2 receptor blockade. Keywords: angiotensin II, AT 2 receptor, cell differentiation, bradykinin, cyclic GMP, nitric oxide. Two major angiotensin II (Ang II) receptor subtypes, AT 1 and AT 2 , have been identified using specific receptor antagonists such as losartan and PD 123319. Most of the established physiological actions of Ang II, such as regulation of blood pressure and electrolyte homoeostasis, as well as its growth promoting actions, are mediated by the AT 1 receptor. However, results of recent studies in various tissues and cell lines have highlighted a number of actions of Ang II that are mediated by activation of AT 2 receptors, including growth inhibition, differentiation, apoptosis and nerve regeneration (Nakajima et al. 1995;Stoll et al. 1995;Yamada et al. 1996;Lucius et al. 1998).Two major strategies have been developed to block the renin-angiotensin system, first, the blockade of angiotensinconverting enzyme (ACE) by the action of ACE inhibitors and, second, the selective blockade of the AT 1 receptor by AT 1 receptor antagonists. ACE inhibitors inhibit the generation of Ang II and block the effects of the peptide on both the AT 1 and the AT 2 receptor. In addition, ACE inhibition in part prevents the degradation of bradykinin, leading to a stimulation of bradykinin B 2 receptor-mediated release of paracrine mediators, such as nitric oxide (NO) and/or prostaglandins. Bradykinin-mediated actions appear to be of major importance for the organ protective effects of ACE inhibitors . On the other hand, AT 1 receptor antagonists selectively block the AT 1 receptor, leave the AT 2 receptor unopposed and do...

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“…Different exposure times are shown in order to detect Cdk4 in all the conditions tested. Immunoblots were quantified by densitometric analysis and the mean half-lives were calculated from three different experiments Huang et al, 1996;Yamada et al, 1996;Bedecs et al, 1997), and in the heart of transgenic mice overexpressing the AT 2 receptor (Masaki et al, 1998). However, it is unlikely that inhibition of the ERK mitogen-activated protein kinase pathway is responsible for the antiproliferative action of the AT 2 receptor, at least in rat fibroblasts.…”

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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Angiotensin II type 2 receptors mediate inhibition of mitogen-activated protein kinase cascade and functional activation of SHP-1 tyrosine phosphatase

Cited by 211 publications

References 55 publications

G_βγ-independent constitutive association of G_αswith SHP-1 and angiotensin II receptor AT₂is essential in AT₂-mediated ITIM-independent activation of SHP-1

G_βγ-independent constitutive association of G_αswith SHP-1 and angiotensin II receptor AT₂is essential in AT₂-mediated ITIM-independent activation of SHP-1

Contribution of bradykinin and nitric oxide to AT₂ receptor‐mediated differentiation in PC12 W cells

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

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Angiotensin II type 2 receptors mediate inhibition of mitogen-activated protein kinase cascade and functional activation of SHP-1 tyrosine phosphatase

Cited by 211 publications

References 55 publications

Gβγ-independent constitutive association of Gαswith SHP-1 and angiotensin II receptor AT2is essential in AT2-mediated ITIM-independent activation of SHP-1

Gβγ-independent constitutive association of Gαswith SHP-1 and angiotensin II receptor AT2is essential in AT2-mediated ITIM-independent activation of SHP-1

Contribution of bradykinin and nitric oxide to AT2 receptor‐mediated differentiation in PC12 W cells

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

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G_βγ-independent constitutive association of G_αswith SHP-1 and angiotensin II receptor AT₂is essential in AT₂-mediated ITIM-independent activation of SHP-1

G_βγ-independent constitutive association of G_αswith SHP-1 and angiotensin II receptor AT₂is essential in AT₂-mediated ITIM-independent activation of SHP-1

Contribution of bradykinin and nitric oxide to AT₂ receptor‐mediated differentiation in PC12 W cells