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(Hypertension. 1996;27:476-480.)
© 1996 American Heart Association, Inc.

Articles

Importance of Tyrosine Phosphorylation in Angiotensin II Type 1 Receptor Signaling

Bernhard Schieffer; William G. Paxton; Mario B. Marrero; Kenneth E. Bernstein

From the Department of Pathology and Laboratory Medicine (B.S., W.G.P., M.B.M., K.E.B.) and the Center of Molecular and Cellular Signaling (M.B.M.), Emory University, Atlanta, Ga.

Correspondence to Kenneth E. Bernstein, MD, Room 711 WMB, Department of Pathology and Laboratory Medicine, 1639 Pierce Dr, Emory University, Atlanta, GA 30322.

	Abstract

Top Abstract Introduction Tyrosine Phosphorylation: A... Ang II Receptors Ang II Stimulates PLC-{gamma}1... Ang II and Src... Ang II and the... Conclusions References

 
Abstract Angiotensin II is the major effector peptide of the renin-angiotensin system. In addition to its vasoconstrictor activity, angiotensin II stimulates smooth muscle cell growth in arterial hypertension and in models of vascular injury. The angiotensin II type 1 receptor is a seven-transmembrane receptor and is responsible for virtually all the physiological actions of angiotensin II. This class of receptor signals in part through its association with heterotrimeric G proteins. A newly developed concept for guanine nucleotide protein–coupled receptors is the activation of intracellular second-messenger proteins via tyrosine phosphorylation. For instance, angiotensin II stimulates the rapid tyrosine phosphorylation and activation of phospholipase C-1. Also, angiotensin II stimulates the tyrosine phosphorylation of Janus kinases. In this review, we discuss early signaling events induced by angiotensin II with an emphasis on tyrosine phosphorylation. Understanding the importance of tyrosine phosphorylation in the signaling pathways of the angiotensin II type 1 receptor may lead to new treatment modalities for cardiovascular disease.

Key Words: receptor, angiotensin II • signal transduction • phospholipase C-1 • protein-tyrosine-phosphatase • protein tyrosine kinase

	Introduction

Top Abstract Introduction Tyrosine Phosphorylation: A... Ang II Receptors Ang II Stimulates PLC-{gamma}1... Ang II and Src... Ang II and the... Conclusions References

 
Cell growth, cell differentiation, and cell-to-cell communication are regulated by the release of extracellular signaling proteins. These molecules stimulate cells via cell surface receptor proteins that span the cell membrane and initiate intracellular signaling cascades. Several different classes of cell surface receptors have been characterized, including receptors for cytokines, growth factors, and seven-transmembrane G protein–coupled receptors. Despite their structural diversity, all receptors are intrinsically similar in that they participate in the flow of information from the cell surface to the cell cytoplasm and then onward toward the nucleus. In this way, receptors regulate cell growth and function.^{1 2 3 4 5 6 7 8}

	Tyrosine Phosphorylation: A Common Signaling Event

Top Abstract Introduction Tyrosine Phosphorylation: A... Ang II Receptors Ang II Stimulates PLC-{gamma}1... Ang II and Src... Ang II and the... Conclusions References

 
Major progress has now been achieved in understanding intracellular signaling cascades. Reversible protein phosphorylation has been shown to be a common mechanism by which cells regulate growth and differentiation.^{7 9} Protein phosphorylation is regulated by the balanced activation of protein kinases and phosphatases within the cell. The phosphorylation and dephosphorylation of second-messenger proteins serve as a mechanism to convey signals from the plasma membrane to the nucleus. Historically, these multienzyme cascades were first described for growth factor receptors with tyrosine kinase domains (ie, EGF and PDGF). Cytokine receptors were then shown to associate with intracellular, soluble tyrosine kinases.⁸ Recently, several observations strongly suggest that vasoactive peptides like Ang II, arginine-vasopressin, thrombin, and endothelin also increase the tyrosine phosphorylation of intracellular second-messenger proteins through seven-transmembrane receptors.

Ang II has characteristics of a growth factor.^{10 11 12 13 14} Pharmacological intervention with angiotensin-converting enzyme inhibitors has been shown to reduce myointimal proliferation after vascular injury with a balloon catheter.¹⁵ An important role of Ang II in cell growth and tissue remodeling has been suggested in experimental models of arterial hypertension, congestive heart failure, and atherosclerosis.^{16 17 18} Together these findings indicate that Ang II is involved in cardiovascular diseases associated with smooth muscle cell proliferation.

In this review we discuss recent observations that underscore the importance of tyrosine phosphorylation in Ang II signaling. We demonstrate that, via tyrosine phosphorylation, Ang II activates PLC-1, leading to the generation of 1,4,5-IP₃. The protein tyrosine kinase pp60^c-src is an integral component of this signaling cascade. We also discuss evidence that Ang II activates the JAK/STAT pathway via tyrosine phosphorylation. Together, these observations emphasize that a classic seven-transmembrane, serpentine receptor, the Ang II AT₁ receptor, in part signals via tyrosine phosphorylation. We hypothesize that these signaling pathways lead to the induction of early growth response genes and ultimately to the control of cell growth.

	Ang II Receptors

Top Abstract Introduction Tyrosine Phosphorylation: A... Ang II Receptors Ang II Stimulates PLC-{gamma}1... Ang II and Src... Ang II and the... Conclusions References

 
Two major classes of Ang II receptors are known and are now commonly referred to as the AT₁ and AT₂ receptor subtypes.^{19 20 21 22} The availability of selective, nonpeptidic inhibitors for each of these receptor types has demonstrated that all of the hemodynamic manifestations of Ang II are a result of AT₁ receptor activation.²² In addition, experimental and clinical studies in congestive heart failure and arterial hypertension have clearly suggested that the nonpeptidic AT₁ receptor antagonist losartan has therapeutic effects similar to those previously demonstrated for angiotensin-converting enzyme inhibitors.^{16 23 24} The AT₁ receptor was first cloned in 1991 in our laboratory and was shown to fall within the superfamily of heterotrimeric guanine nucleotide–coupled (G protein) receptors.¹⁹ The AT₁ receptor consists of 359 amino acids (Fig 1). As with other G protein–coupled receptors, the AT₁ receptor is thought to fold into a three-dimensional configuration containing seven transmembrane-spanning helices. These helices interact with cytoplasmic and extracellular portions of the molecule to form a ligand-binding pocket.^{25 26 27} Portions of the AT₁ receptor are extracellular, while other regions of the molecule are intracellular or within the cell membrane.

View larger version (39K): [in this window] [in a new window]   Figure 1. The rat Ang II AT1 receptor. The AT1 receptor is composed of 359 amino acids. This receptor is thought to form seven transmembrane-spanning helices, which interact to form a ligand-binding pocket. The third intracellular loop (G-protein binding site) and the carboxyl tail of the receptor seem to be important for Ang II signaling.27 At positions at which two amino acids are indicated, the first is the sequence of the rat AT1A receptor, and the second is the sequence of the AT1B receptor. Figure courtesy of Dr Kathy Griendling, Division of Cardiology, Emory University.

	Ang II Stimulates PLC-1 Via Tyrosine Phosphorylation

Top Abstract Introduction Tyrosine Phosphorylation: A... Ang II Receptors Ang II Stimulates PLC-{gamma}1... Ang II and Src... Ang II and the... Conclusions References

 
Ang II signaling is dependent on the activation of PLC.^{28 29} This leads to the hydrolysis of phosphatidylinositol 4,5-biphosphate to 1,4,5-IP₃ and diacylglycerol.^{26 30 31} 1,4,5-IP₃ in turn leads to calcium mobilization from intracellular stores and the stimulation of protein kinase C. Thus, the downstream signaling events mediated by Ang II are critically dependent on PLC activation.

Three different classes or isoforms of PLC have now been identified.³² These are referred to as PLC-ß, PLC-, and PLC-. At present, the four ß-isoforms of PLC are thought to be activated by subunits of heterotrimeric G proteins. In contrast, the -isoforms of PLC must be activated by tyrosine phosphorylation, and it is these forms of PLC that are regulated by growth factor receptors. At the moment, the regulation of the -isoforms of PLC is still not clear.³² We have examined the distribution of PLC isoforms within cultured rat vascular smooth muscle cells. To our surprise, we were unable to identify ß-isoforms of PLC by Western blot analysis. Since vascular smooth muscle cells are highly responsive to Ang II, these observations pose the question of how the AT₁ receptor stimulates intracellular calcium release. We recently investigated the early signaling events stimulated by Ang II in vascular smooth muscle cells. We find that Ang II induces the rapid tyrosine phosphorylation of PLC-1.³³ This phosphorylation is rapid, occurring within 0.5 minute of ligand addition (Fig 2). Six minutes after the addition of Ang II, PLC-1 phosphorylation is approximately at the level observed before the addition of ligand. This temporal sequence of PLC-1 phosphorylation on tyrosine is virtually identical to cellular PLC activation as measured by the intracellular levels of 1,4,5-IP₃. In addition, genistein and tyrphostin, inhibitors of tyrosine phosphorylation, blocked the Ang II–mediated production of 1,4,5-IP₃. These data strongly suggest that Ang II signaling in vascular smooth muscle cells is critically dependent on the tyrosine phosphorylation and activation of PLC-1. This activation is mediated by the AT₁ receptor.

View larger version (24K): [in this window] [in a new window]   Figure 2. Stimulation of PLC-1 by Ang II in smooth muscle cells. Ang II binding to the AT1 receptor appears to activate the soluble tyrosine kinase pp60c-src. This in turn phosphorylates and stimulates PLC-1 to hydrolyze phosphatidylinositol 4,5-biphosphate (PIP2) to form 1,4,5-IP3 and diacylglycerol (DAG). 1,4,5-IP3 stimulates the release of intracellular calcium (Ca2+), which induces smooth muscle cell contraction and activates other cell signaling pathways.

To exclude the possibility that these data are somehow unique to vascular smooth muscle cells, we also studied Ang II–induced signaling in cultured rat glomerular mesangial cells. Previous observation has indicated that, like smooth muscle cells, glomerular mesangial cells produce inositol phosphates in response to Ang II.³⁴ Other groups have also shown that in rat mesangial cells, Ang II stimulates increased protein tyrosine phosphorylation.^{34 35} Therefore, we investigated whether Ang II would induce PLC-1 tyrosine phosphorylation in a fashion similar to what we had observed with smooth muscle cells.³⁶ Stimulation of mesangial cells with 10^-7 mol/L Ang II for 0.5 minute increased intracellular 1,4,5-IP₃ levels approximately fourfold over control cells. This rise in 1,4,5-IP₃ levels paralleled a marked increase in tyrosine phosphorylation of PLC-1 as measured by Western blot analysis. The preincubation of these cells with the tyrosine kinase inhibitor genistein (120 µmol/L) blocked both the Ang II–induced tyrosine phosphorylation of PLC-1 and the generation of 1,4,5-IP₃.^{35 36} In addition, studies of glomerular mesangial cells with the tyrosine kinase inhibitor herbimycin showed similar results, indicating that in these cell types, tyrosine phosphorylation plays a crucial role in the initial signaling cascades initiated when Ang II binds to the AT₁ receptor. Whether these observations are due to a direct blockade of PLC-1 tyrosine phosphorylation or to an inhibition of an intermediate tyrosine kinase remains unresolved. However, the question remains of how a seven-transmembrane receptor lacking an intrinsic tyrosine kinase activity can lead to the activation of tyrosine phosphorylation cascades.

	Ang II and Src Kinase Activation

Top Abstract Introduction Tyrosine Phosphorylation: A... Ang II Receptors Ang II Stimulates PLC-{gamma}1... Ang II and Src... Ang II and the... Conclusions References

 
Several different groups have observed that Ang II leads to the phosphorylation of multiple proteins on tyrosine.^{33 37 38} This implies that Ang II must recruit an intracellular protein tyrosine kinase subsequent to interaction of ligand with the AT₁ receptor. Previous reports indicated a connection between the Src family of tyrosine kinases and second-messenger proteins known to be active in AT₁ receptor signaling.³⁹ For instance, Liao et al⁴⁰ showed that PLC-1 is an excellent in vitro substrate for members of the Src family. In addition, Dhar and Shukla⁴¹ recently reported that PAF, a seven-transmembrane receptor ligand, induces tyrosine phosphorylation in platelets via pp60^c-src. This group showed that PAF induces the tyrosine phosphorylation of PLC-1 and the generation of 1,4,5-IP₃. In experiments in which electroporation was used to insert anti-pp60^c-src antibodies into cells, the enzyme activity of pp60^c-src was neutralized, tyrosine phosphorylation of PLC-1 was abolished, and PAF-mediated production of 1,4,5-IP₃ was completely suppressed. These effects seemed specific for the anti-pp60^c-src antisera, since control antibodies showed no effect.⁴¹

We recently investigated whether pp60^c-src is involved in Ang II–induced early signaling events, specifically the tyrosine phosphorylation of PLC-1 and the generation of 1,4,5-IP₃. In contrast to Dhar and Shukla, our cells of interest, vascular smooth muscle cells, grow in cell culture attached to the culture dish. Therefore, we established an electroporation method that enabled us to introduce antibodies into these cells without affecting their physiological response or destroying cell-to-cell connections.⁴² The efficiency of this technique was measured by flow cytometry after electroporation and assessed by the incorporation of a fluorescence-labeled IgG.⁴² Similar to the data of Dhar and Shukla, we observed that in the presence of the anti-pp60^c-src antibody, the tyrosine phosphorylation of PLC-1 in response to Ang II was completely blocked and the generation of 1,4,5-IP₃ was markedly inhibited. These results indicate that pp60^c-src or a closely related member of the Src family of tyrosine kinases is the likely tyrosine kinase enzymes responsible for Ang II–mediated tyrosine phosphorylation of PLC-1. Finally, Ishida et al⁴³ recently presented evidence that Ang II directly stimulates pp60^c-src enzyme activity.

Our laboratory has demonstrated that the AT₁ receptor is phosphorylated on tyrosine.³⁹ We have also shown in in vitro experiments that enzymes of the Src family of tyrosine kinases can phosphorylate the carboxyl terminal tail of the AT₁ receptor. Furthermore, observations from our group and other investigators have indicated that several known substrates of pp60^c-src, such as pp120, FAK¹²⁵, paxillin, JAK2, and STAT1, are also phosphorylated on tyrosine when stimulated with Ang II.^{44 45 46} These data strongly suggest that pp60^c-src or related enzymes of the Src family are involved in the early signaling events mediated by the AT₁ receptor.

	Ang II and the JAK-STAT Pathway

Top Abstract Introduction Tyrosine Phosphorylation: A... Ang II Receptors Ang II Stimulates PLC-{gamma}1... Ang II and Src... Ang II and the... Conclusions References

 
In a sense, the AT₁ receptor resembles cytokine receptors: These receptors lack intrinsic tyrosine kinase activity, yet they induce tyrosine phosphorylation and are capable of stimulating cell growth.^{11 12 47} Activation of both cytokine receptors and the AT₁ receptor leads to the rapid increase of c-fos mRNA, an early growth response gene.⁴⁷ Although not yet conclusively demonstrated, the induction of c-fos is probably an important initial step in the series of molecular events leading to Ang II–induced cell proliferation. Two intracellular signaling pathways leading to c-fos production have been well defined. The first is a multiple-kinase pathway used by a number of growth factors, such as PDGF and EGF. In this pathway, a ligand activates a cell surface receptor containing intrinsic kinase activity, which in turn activates a cascade linking protein tyrosine kinases to serine/threonine kinases, such as p42 mitogen activated protein kinase.⁴⁸ A second, more direct signaling pathway is stimulated by cytokines, such as the interferons.⁴⁹ Here, ligand binding to a cell surface receptor activates the JAK family of intracellular tyrosine kinases. Five members of this family have been identified and characterized (JAK1, JAK2, JAK3, TYK2, and hopscotch).^{49 50} In response to ligand binding, the JAK kinases associate with dimerized cytokine receptors, autophosphorylate, and activate other downstream signaling molecules via tyrosine phosphorylation. Well-described JAK substrates are the STAT family of proteins.⁵⁰ When activated by tyrosine phosphorylation, STAT1 (p91) associates with STAT2 (p113) and p48 to form the ISGF3 complex. This protein complex then translocates to the nucleus, where it binds to specific DNA motifs and stimulates early growth response genes such as c-fos. Thus, the JAK-STAT pathway acts as a direct link between a cell surface receptor and nuclear transcriptional events (Fig 3).

View larger version (30K): [in this window] [in a new window]   Figure 3. A model for the Ang II–induced activation of the JAK/STAT pathway in smooth muscle cells. Ang II binding to the AT1 receptor triggers the tyrosine phosphorylation and activation of the intracellular kinases JAK2 and TYK2. These kinases in turn activate downstream signaling proteins STAT 1/ß and STAT 2 by tyrosine phosphorylation. These STAT proteins are then thought to heterodimerize into a complex and to further associate with the protein p48 to form the ISGF3 complex. ISGF3 translocates to the nucleus, where it binds to specific DNA binding sites and initiates the transcription of early growth response genes such as c-fos. ISRE indicates interferon-stimulated response element.

We have investigated whether Ang II stimulates activation of the JAK-STAT pathway. We showed in cultured smooth muscle cells that Ang II induces the rapid tyrosine phosphorylation of the intracellular kinases JAK2 and TYK2. This phosphorylation is associated with increased enzyme activity of JAK2.^{46 51} In response to JAK2 activation, STAT1 and STAT2 are rapidly phosphorylated on tyrosine. Finally, Ang II leads to the translocation of STAT proteins into the nucleus. Concurrent with our observations, Bhat et al⁴⁴ demonstrated that in cultured neonatal fibroblasts, Ang II induces STAT protein phosphorylation, translocation of STAT proteins into the nucleus, and the initiation of gene transcription. The data from both our group and Bhat et al suggest that Ang II, acting through the AT₁ receptor, can directly signal to the cell nucleus via tyrosine phosphorylation and that Ang II stimulates signaling cascades that were previously identified exclusively for cytokines and their receptors.⁴⁹

	Conclusions

Top Abstract Introduction Tyrosine Phosphorylation: A... Ang II Receptors Ang II Stimulates PLC-{gamma}1... Ang II and Src... Ang II and the... Conclusions References

 
Protein tyrosine phosphorylation is an essential component of the Ang II–stimulated signaling pathway that regulates vascular smooth muscle cell contraction and cell growth. Blockade of Ang II formation has been therapeutically successful in experimental models of arterial hypertension, congestive heart failure, and restenosis after balloon angioplasty. The newly developed concepts of tyrosine phosphorylation in the pathway of Ang II–mediated activation open the possibility of new approaches for therapeutic intervention in cardiovascular disease. Inhibitors of Ang II signaling will offer new modalities to treat the structural alterations of cardiovascular disease, including smooth muscle cell proliferation. In this way, new observations concerning Ang II signaling pathways will result in increased understanding and ability to modify the pathology in cardiovascular disease.

	Selected Abbreviations and Acronyms

 

Ang II = angiotensin II AT1 receptor = angiotensin II type 1 receptor EGF = epidermal growth factor 1,4,5-IP3 = 1,4,5-inositol triphosphate ISGF3 complex = interferon-stimulated growth factor complex 3 JAK = Janus kinase PAF = platelet-activating factor PDGF = platelet-derived growth factor PLC = phospholipase C STAT = signal transducers and activators of transcription

	Acknowledgments

 
Dr Schieffer is supported by a Deutsche Forschungsgemeinschaft Stipendium (SCHI: 386/1-1). Dr Marrero is an American Heart Association Minority Developmental Award Scientist. We are grateful for National Institutes of Health grants DK-39777, DK-44280, and DK-45215 as well as Grants-in-Aid from the American Heart Association and the Georgia affiliate of the American Heart Association for supporting this work. The authors wish to thank Drs Brian Ling, Brad Berk, and Merouane Bencherif for helpful discussions and research specialists Qing Chai and Elaine Marino-Rodriguez for technical support.

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Top Abstract Introduction Tyrosine Phosphorylation: A... Ang II Receptors Ang II Stimulates PLC-{gamma}1... Ang II and Src... Ang II and the... Conclusions References

 
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