Tyrosine Kinase Activation by the Angiotensin II Receptor in the Absence of Calcium Signaling

Doan, Thanh N.; Ali, M. Showkat; Bernstein, Kenneth E.

doi:10.1074/jbc.c100199200

Cited by 59 publications

(46 citation statements)

References 19 publications

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“…Mutation of five tyrosine residues (292, 302, 312, 319, and 339) rendered the AT 1 receptor incapable of ligand-induced G protein activation, IP 3 production, and calcium signaling. However, the mutant receptor retained Ang II-induced activation of tyrosine kinase signaling (activation of JAK2 and its effector STAT1) and cell proliferation (Doan et al 2001). Interestingly, the proximal region (residues 304-316) of the cytoplasmic tail is one of the critical regions that interact with G proteins (Kai et al 1998).…”

Section: Cooh-terminal Tailmentioning

confidence: 99%

Structural determinants for binding, activation, and functional selectivity of the angiotensin AT1 receptor

Balakumar¹,

Jagadeesh²

2014

Journal of Molecular Endocrinology

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The renin-angiotensin system (RAS) plays an important role in the pathophysiology of cardiovascular disorders. Pharmacologic interventions targeting the RAS cascade have led to the discovery of renin inhibitors, angiotensin-converting enzyme inhibitors, and AT 1 receptor blockers (ARBs) to treat hypertension and some cardiovascular and renal disorders. Mutagenesis and modeling studies have revealed that differential functional outcomes are the results of multiple active states conformed by the AT 1 receptor upon interaction with angiotensin II (Ang II). The binding of agonist is dependent on both extracellular and intramembrane regions of the receptor molecule, and as a consequence occupies more extensive area of the receptor than a non-peptide antagonist. Both agonist and antagonist bind to the same intramembrane regions to interfere with each other's binding to exhibit competitive, surmountable interaction. The nature of interactions with the amino acids in the receptor is different for each of the ARBs given the small differences in the molecular structure between drugs. AT 1 receptors attain different conformation states after binding various Ang II analogues, resulting in variable responses through activation of multiple signaling pathways. These include both classical and non-classical pathways mediated through growth factor receptor transactivations, and provide cross-communication between downstream signaling molecules. The structural requirements for AT 1 receptors to activate extracellular signal-regulated kinases 1 and 2 through G proteins, or G proteinindependently through b-arrestin, are different. We review the structural and functional characteristics of Ang II and its analogs and antagonists, and their interaction with amino acid residues in the AT 1 receptor.

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Section: Cooh-terminal Tailmentioning

confidence: 99%

Structural determinants for binding, activation, and functional selectivity of the angiotensin AT1 receptor

Balakumar¹,

Jagadeesh²

2014

Journal of Molecular Endocrinology

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“…We also confirmed that AngII-induced EGFR transactivation remained intact in COS7 cells expressing AT 1 -(1-317) (data not shown). However, recent studies using distinct mutants of AT 1 demonstrated G proteinindependent activation of tyrosine kinases (36,37,52). In particular, it has been reported that in a mutant of a conserved YIPP motif in the C terminus of AT 1 , AT 1 Y319F, EGFR transactivation was attenuated, whereas G q coupling remained intact (37).…”

Section: Requirement Of G Q Coupling For Hb-egf Shedding Through Atmentioning

confidence: 99%

G Protein Coupling and Second Messenger Generation Are Indispensable for Metalloprotease-dependent, Heparin-binding Epidermal Growth Factor Shedding through Angiotensin II Type-1 Receptor

Mifune

Ohtsu

Suzuki

et al. 2005

Journal of Biological Chemistry

118

106

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“…33 Indeed, selectively G protein-uncoupled AT 1 Rs may nevertheless activate markers of growth. 6,7 These findings were exciting in that they implicated aspects of receptor function, distinct from G-protein coupling, as important growth pathway mediators and suggested that pathway-specific ligands could be developed with greater efficacy and fewer off-target effects. Although surrogate growth markers can be stimulated without G-protein coupling, we report that G-protein coupling is crucial at the cardiomyocyte level for hypertrophy, consistent with a recent study in vascular smooth muscle cells.…”

Section: Discussionmentioning

confidence: 99%

Determination of the Exact Molecular Requirements for Type 1 Angiotensin Receptor Epidermal Growth Factor Receptor Transactivation and Cardiomyocyte Hypertrophy

et al. 2011

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Abstract-Major interest surrounds how angiotensin II triggers cardiac hypertrophy via epidermal growth factor receptor transactivation. G protein-mediated transduction, angiotensin type 1 receptor phosphorylation at tyrosine 319, and ␤-arrestin-dependent scaffolding have been suggested, yet the mechanism remains controversial. We examined these pathways in the most reductionist model of cardiomyocyte growth, neonatal ventricular cardiomyocytes. Analysis with [ 32 P]-labeled cardiomyocytes, wild-type and [Y319A] angiotensin type 1 receptor immunoprecipitation and phosphorimaging, phosphopeptide analysis, and antiphosphotyrosine blotting provided no evidence for tyrosine phosphorylation at Y319 or indeed of the receptor, and mutation of Y319 (to A/F) did not prevent either epidermal growth factor receptor transactivation in COS-7 cells or cardiomyocyte hypertrophy. Instead, we demonstrate that transactivation and cardiomyocyte hypertrophy are completely abrogated by loss of G-protein coupling, whereas a constitutively active angiotensin type 1 receptor mutant was sufficient to trigger transactivation and growth in the absence of ligand. These results were supported by the failure of the ␤-arrestin-biased ligand SII angiotensin II to transactivate epidermal growth factor receptor or promote hypertrophy, whereas a ␤-arrestin-uncoupled receptor retained these properties. We also found angiotensin II-mediated cardiomyocyte hypertrophy to be attenuated by a disintegrin and metalloprotease inhibition. Thus, G-protein coupling, and not Y319 phosphorylation or ␤-arrestin scaffolding, is required for epidermal growth factor receptor transactivation and cardiomyocyte hypertrophy via the angiotensin type 1 receptor. A ngiotensin II (Ang II) contributes to progression of left ventricular hypertrophy, a major independent risk factor for myocardial infarction and sudden death, 1 yet the molecular mechanisms governing cardiac hypertrophy remain controversial. Recently, a new paradigm for Ang II hypertrophy has emerged. We and others have shown that angiotensin type 1 receptors (AT 1 Rs) hijack the epidermal growth factor (EFR) receptor (EGFR) via a process termed the "triple membrane-passing signaling paradigm of EGFR transactivation." 2-5 More specifically, AT 1 R activation causes metalloprotease-dependent EGF-like ligand release and subsequent EGFR binding to initiate hypertrophic signaling cascades. Yet the process is likely more complicated: multiple G protein-coupled receptor (GPCR) signals, a disintegrin and metalloproteases (ADAMs), EGF-like ligands, and EGFR subtypes have been implicated in this process. 2 A major focus of Ang II research is the mechanism by which the AT 1 R signals to the EGFR. Recent studies suggested a G protein-independent pathway for growth activation, 6 -9 despite evidence that G␣ q/11 , a heterotrimeric G protein that couples to the AT 1 R, is essential for hypertrophy. 10 Indeed, others indicate that G-protein coupling to AT 1 R is required for EGFR transactivation in COS-7 and vascular smoot...

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Tyrosine Kinase Activation by the Angiotensin II Receptor in the Absence of Calcium Signaling

Cited by 59 publications

References 19 publications

Structural determinants for binding, activation, and functional selectivity of the angiotensin AT1 receptor

Structural determinants for binding, activation, and functional selectivity of the angiotensin AT1 receptor

G Protein Coupling and Second Messenger Generation Are Indispensable for Metalloprotease-dependent, Heparin-binding Epidermal Growth Factor Shedding through Angiotensin II Type-1 Receptor

Determination of the Exact Molecular Requirements for Type 1 Angiotensin Receptor Epidermal Growth Factor Receptor Transactivation and Cardiomyocyte Hypertrophy

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