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

Yu, Feng; Sun, Yan; Douglas, Janice G.

doi:10.1073/pnas.192404199

Cited by 55 publications

(43 citation statements)

References 41 publications

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“…We further explored the possibility that ATIP1 may function as a scaffold protein to bring SHP-1 at the vicinity of the AT2 receptor, as previously shown for the G␣S protein (32). However, all attempts to visualize an interaction between ATIP1 and SHP-1, both at basal conditions and after stimulation with Ang II or growth factors, remained unsuccessful (data not shown).…”

Section: Discussionmentioning

confidence: 93%

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

Nouet

Amzallag

et al. 2004

Journal of Biological Chemistry

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: Discussionmentioning

confidence: 93%

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

Nouet

Amzallag

et al. 2004

Journal of Biological Chemistry

172

189

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“…Although AT 2 receptors have been shown to induce MAPK activity in neuronal NG108 -15 cells, 48 most studies have pointed to an inhibitory action of the AT 2 receptor on ERK1/2 MAPK and growth, primarily via activation of the SH2 domain-containing tyrosine phosphatase (SHP-1), MAPK phosphatase-1, and serine/threonine phosphatase 2A pathways. 4,6,11,12,29,49 Interestingly, Feng et al 49 could provide no evidence to support a constitutive activation of SHP-1 by the AT 2 receptor; instead, SHP-1 associated with the "inactive" AT 2 receptor and was released on Ang II stimulation. In cardiac fibroblasts, the AT 2 receptor inhibited protein tyrosine phosphatases but had no effect on MAPK ERK1/2 activity.…”

Section: Discussionmentioning

confidence: 99%

The Angiotensin II Type 2 Receptor Causes Constitutive Growth of Cardiomyocytes and Does Not Antagonize Angiotensin II Type 1 Receptor–Mediated Hypertrophy

2005

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Abstract-Angiotensin II (Ang II) has important actions on the heart via type 1 (AT 1 ) and type 2 (AT 2 ) receptors. The link between AT 1 receptor activation and the hypertrophy of cardiomyocytes is accepted, whereas the contribution of the AT 2 receptor, which reportedly antagonizes the AT 1 receptor, is contentious. This ambiguity is primarily based on in vivo approaches, in which the direct effect of the AT 2 receptor and its modulation of the AT 1 receptor (at the level of the cardiomyocyte) are difficult to establish. In this study, we used adenoviruses encoding AT 1 and AT 2 to coexpress these receptors in isolated cardiomyocytes, allowing a direct examination of the consequence of varying AT 1 /AT 2 stoichiometry on cardiomyocyte hypertrophy. Key Words: angiotensin II Ⅲ hypertrophy Ⅲ myocytes Ⅲ rats Ⅲ receptors L eft ventricular hypertrophy (LVH) is a major independent risk factor for premature death. 1 Extensive experimental and clinical evidence supports a role for the vasoactive hormone angiotensin II (Ang II) in the development of hypertension and the associated cardiomyocyte enlargement, which is a hallmark of LVH. Ang II binds with high affinity to type 1 (AT 1 ) and type 2 (AT 2 ) Ang II receptors, which are 7-transmembrane spanning, G-protein-coupled receptors. 2 AT 1 receptors are well characterized and mediate the established actions of Ang II, including vasoconstriction, aldosterone and vasopressin release, renal sodium reabsorption, increased collagen deposition, cellular proliferation, and, importantly, cardiomyocyte hypertrophy. The role of the AT 2 receptor is less clear, but current theories favor a role in opposing the actions of the AT 1 receptor. 3-7 AT 2 receptors are highly expressed in the fetus; however, after birth, the AT 2 receptor expression decreases to low levels. 2 In normal, adult human and rat hearts, AT 1 and AT 2 receptors are expressed, 8 -10 and they have been shown to be upregulated during cardiovascular pathologies. 8,9 The specific signaling pathways activated via the AT 2 receptor remain poorly resolved, although AT 2 receptors reportedly inhibit AT 1 receptor signaling pathways, such as extracellular signalregulated kinase 1/2 (ERK1/2) mitogen-activated protein kinases (MAPKs), by activating specific tyrosine or serine/ threonine phosphatases. 6,11,12 More recent evidence suggests functional heterodimerization between the AT 1 and AT 2

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“…In transformed epithelial cells, SHP-1 is activated by the AT2 receptor in a mechanism that requires the physical association of G s protein (-subunit of stimulatory heterotrimeric G protein) (Feng et al, 2002). The activation of the G protein is not required for SHP-1 activation, suggesting that G s functions as an adaptor molecule in this process.…”

Section: Ang-ii-induced Apoptosis Requires the G S Protein As An Adamentioning

confidence: 99%

“…We investigated the requirement of G s for SHP-2 activation by AT2. A peptide corresponding to the last 11 amino acids of G s was shown by Feng et al (Feng et al, 2002) (CGP) for 16 hours before the preparation of mitochondria-free cell fractions (cytosol) or mitochondria. Lysates were western blotted for cytochrome c or activated caspase-3.…”

Section: Ang-ii-induced Apoptosis Requires the G S Protein As An Adamentioning

confidence: 99%

Angiotensin-II-induced apoptosis requires regulation of nucleolin and Bcl-xL by SHP-2 in primary lung endothelial cells

Lee

Mungunsukh

Tutino

et al. 2010

Journal of Cell Science

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SummaryAngiotensin II (Ang II) is a key proapoptotic factor in fibrotic tissue diseases. However, the mechanism of Ang-II-induced cell death in endothelial cells has not been previously elucidated. Using the neutral comet assay and specific receptor antagonists and agonists, we found that Ang-II-mediated apoptosis in primary pulmonary endothelial cells required the AT2 receptor. Ang II caused cytochrome c release from the mitochondria concurrent with caspase-3 activation and DNA fragmentation, and apoptosis was suppressed by an inhibitor of Bax-protein channel formation, implicating mitochondrial-mediated apoptosis. There was no evidence that the extrinsic apoptotic pathway was involved, because caspase-9, but not caspase-8, was activated by Ang-II treatment. Apoptosis required phosphoprotein phosphatase activation, and inhibition of the SHP-2 phosphatase (encoded by Ptpn11) blocked cell death. Reduced levels of anti-apoptotic Bcl-2-family members can initiate intrinsic apoptosis, and we found that Ang-II treatment lowered cytosolic Bcl-x L protein levels. Because the protein nucleolin has been demonstrated to bind Bcl-x L mRNA and prevent its degradation, we investigated the role of nucleolin in Ang-II-induced loss of Bcl-x L . RNA-immunoprecipitation experiments revealed that Ang II reduced the binding of nucleolin to Bcl-x L mRNA in an AU-rich region implicated in instability of Bcl-x L mRNA. Inhibition of SHP-2 prevented Ang-II-induced degradation of Bcl-x L mRNA. Taken together, our findings suggest that nucleolin is a primary target of Ang-II signaling, and that Ang-II-activated SHP-2 inhibits nucleolin binding to Bcl-x L mRNA, thus affecting the equilibrium between pro-and anti-apoptotic members of the Bcl-2 family.

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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

Cited by 55 publications

References 41 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

The Angiotensin II Type 2 Receptor Causes Constitutive Growth of Cardiomyocytes and Does Not Antagonize Angiotensin II Type 1 Receptor–Mediated Hypertrophy

Angiotensin-II-induced apoptosis requires regulation of nucleolin and Bcl-xL by SHP-2 in primary lung endothelial cells

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