Versatility of the Angiotensin II Type 1 Receptor

Correspondence to Junichi Sadoshima, MD, PhD, Cardiovascular and Pulmonary Research Institute, Allegheny University of the Health Sciences, 15th Floor, South Tower, 320 East North Ave, Pittsburgh, PA 15212. E-mail jsadoshi{at}pgh.auhs.edu

Key Words: angiotensin II type 1 receptor • cell growth • tyrosine kinase

This issue of Circulation Research includes 3 interesting studies that represent new concepts of AT₁ receptor–mediated cell signaling in the cardiovascular system, which is currently of intense interest. The AT₁ receptor mediates many important cardiovascular responses, including vasoconstriction, vascular and cardiac remodeling (cell proliferation, hypertrophy, and production of extracellular matrix), and cell survival/cell death. The AT₁ receptor belongs to the seven membrane–spanning GPCR family and typically activates PLCß through the heterotrimeric G_q protein, causing production of inositol trisphosphate and diacylglycerol. Besides this classical GPCR-G_q-PLCß pathway, recent studies indicate that Ang II activates both nonreceptor-type and receptor-type tyrosine kinases, which are typically activated by cytokine and EGFR stimulation. Activation of tyrosine kinases by Ang II is of great interest for a variety of reasons. First, tyrosine kinase–dependent signaling pathways mediate major growth effects of Ang II in cardiovascular systems.¹ Sayeski et al² reports that a 130-kDa protein, which is tyrosine-phosphorylated by Ang II, is identified as p130^Cas and that it potentially works as an effector of Src and PKC in VSMCs. Second, since the AT₁ receptor possesses neither intrinsic protein tyrosine kinase activities nor known physical association with tyrosine kinases except interaction with JAK2,³ the linkage between the AT₁ receptor and the tyrosine kinases was unexpected. Murasawa et al⁴ reports that Ang II transactivates the EGFR, which in turn mediates DNA synthesis in cardiac fibroblasts. Third, tyrosine kinases mediate activation of small GTP binding proteins (the Ras and Rho family) and downstream MAP kinases. Schmitz et al⁵ reports that Ang II activates the PAK-JNK pathway via a tyrosine kinase–dependent mechanism in VSMCs. Since a comprehensive review on tyrosine kinase activation by Ang II has appeared recently,^{1 6} the focus of this editorial is to highlight findings of the most recent literature, including both cardiovascular and noncardiovascular systems, and the future direction of those new concepts regarding AT₁ receptor cell signaling.

Nonreceptor-Type Tyrosine Kinases

Since several groups have reported that Ang II increases the phosphotyrosine content of cellular proteins in liver GN4 cells, VSMCs, and cardiac myocytes/fibroblasts, many of these phosphotyrosine-containing proteins and the tyrosine kinases, which are responsible for the tyrosine phosphorylation, have been identified (reviewed in Reference 1¹ ). The phosphotyrosine-containing proteins identified thus far include protein kinases/phosphatases (Jak2, Tyk2, FAK, PYK2, Src, ERK, and PTP-1D), enzymes/regulatory proteins (PLC-1 and IRS-1), adapter proteins (Shc and paxillin), and transcription factors (Stat1, Stat3, and Stat5).⁶

Sayeski et al² found that another protein, p130^Cas, is tyrosine-phosphorylated by Ang II in VSMCs. It has been recently shown that p130^Cas mediates FAK-promoted cell migration on fibronectin in CHO-K1 cells.⁷ Interestingly, p130^Cas physically interacts not only with Src and pp120 but also with PKC in VSMCs. Sayeski et al have proposed that p130^Cas works as a docking site, which attracts molecules associated with the 3 separate important signaling pathways (namely, Src, PKC, and focal adhesion–related signaling pathways) into one place. The physical interaction between p130^Cas and these individual signaling molecules apparently takes place with different kinetics. These spatial and temporal regulations of protein-protein interactions will allow the AT₁ receptor to control cellular events with more precision.

Ang II activates Src-family tyrosine kinases in cardiac myocytes and VSMCs.^{8 9} Activation of Src-family tyrosine kinases by Ang II mediates tyrosine phosphorylation of many proteins, including phospholipase C1, Shc, p97, pp120, and p130^Cas, and activation of the downstream signaling molecules, such as Ras and ERKs.¹⁰ The mechanism of Src activation by AT₁ receptor stimulation has not been fully elucidated. In VSMCs, activation of PLC and the subsequent production of inositol trisphosphate and diacylglycerol depend on Src, since PLC-1 is the predominant isoform of PLC in this cell type.¹¹ Tyrosine kinase may control the function of heterotrimeric G_q protein, since tyrosine phosphorylation of the C-terminal end amino acid sequence in G_q has been shown to be essential for the function of G_q.¹² These results raise an interesting question: Is Src activated by a mechanism independent of (or rather upstream from) the G_q-PLCß pathway? The definitive answer to this question does not seem to have been obtained as of yet. Although JAK2 is activated by Ang II through direct association with the C-terminal cytoplasmic domain of the AT₁ receptor, such direct association between Src and the AT₁ receptor is unlikely.⁸ Multiple mechanisms have been hypothesized for Src activation by other growth factors. These include involvement of receptor-type or nonreceptor-type tyrosine kinases,¹³ tyrosine phosphatases,¹⁴ the G_ß subunit,¹⁵ and high-affinity SH2/SH3 domain–containing proteins.¹⁴ It remains to be seen whether or not these molecules contribute to Ang II–induced Src activation.

Besides Src, FAK and PYK2 (also known as Ca²⁺-dependent tyrosine kinase) are also activated by Ang II.¹⁶ The mechanism of activation, time course of activation, subcellular localization, and substrate specificity all seem different among these tyrosine kinases.¹⁷

Receptor-Type Tyrosine Kinases

Murasawa et al⁴ have reported that Ang II transactivates the EGFR tyrosine kinase, which in turn mediates Ang II–induced mitogenic responses in cardiac fibroblasts. Transactivation of the EGFR tyrosine kinase by GPCR was originally reported in Rat-1 fibroblasts stimulated with endothelin-1, thrombin, or lysophosphatidic acid.¹⁸ Since then, similar observations have been reported, and transactivation of the EGFR family is likely to be a common and important mechanism for the GPCR to use the cell tyrosine kinase–signaling machinery. This apparently ligand-independent activation of the receptor type tyrosine kinase is also observed when cells are stimulated with ultraviolet irradiation, growth hormone, and cytokines.¹⁹ Murasawa et al have shown that selective inhibition of the EGFR tyrosine kinase activity by AG1478 and the dominant-negative EGFR mutant inhibits Ang II–induced transactivation of the EGFR. Thus, both tyrosine kinase activities and dimerization of the EGFR seem to be required. The EGFR seems to be autophosphorylated in response to Ang II as if it were activated by EGF binding. Murasawa et al excluded the possibility that Ang II causes autocrine secretion of EGF, implying an alternative mechanism of ligand-independent EGFR activation. Studies of GPCR-induced EGFR activation in COS-7 cells and GN4 liver cells indicate that Src-family tyrosine kinases, FAK and PYK2, are unlikely to mediate this response.²⁰ In cardiac fibroblasts and VSMCs, Ca²⁺ calmodulin inhibitors and Ca²⁺ chelators abolish Ang II–induced transactivation of the EGFR.^{4 21} In GN4 rat liver cells, Ang II–induced transactivation of the EGFR is suppressed by PKC.²⁰ A possible mechanism explaining these observations may be the involvement of unknown (Ca²⁺-dependent and/or PKC-sensitive) tyrosine kinases or phosphatases, whose activation or inhibition, respectively, could account for the GPCR-mediated EGFR-tyrosine phosphorylation. In any case, these intermediate molecules, either tyrosine kinases or phosphatases, are likely to have a substrate specificity toward the EGFR over other receptor-type tyrosine kinases, since EGFR is most preferentially transactivated by Ang II. Alternatively, Ang II may stimulate dimer formation of a phosphotyrosine-containing protein that interacts with the EGFR. A similar mechanism has been recently shown for interleukin-6–induced ErbB2 receptor tyrosine kinase activation, where activated gp130 receptor dimers recruit ErbB2 receptor tyrosine kinase to the complex, leading to ErbB2 clustering and kinase activation.¹⁹ Availability of the receptor tyrosine kinase pathway depends on the existence of the appropriate receptor tyrosine kinase and intermediate molecules. For example, neonatal and adult cardiac myocytes respond poorly to EGF stimulation,²² suggesting that the EGF pathway may not be a major Ang II–regulated tyrosine kinase pathway in these preparations.

Ras- and Rho-Family Small GTP Binding Proteins and Downstream MAP Kinases

Small GTP binding proteins, such as those in the Ras and Rho families, are activated by ligands for the tyrosine kinase receptors, the cytokine receptors, and the GPCRs. A growing number of molecules have been identified as effector molecules for each small GTP binding protein (reviewed in Reference 23²³ ). Regulation of the MAP kinase cascades is one of the most important functions of the small GTP binding proteins. Ang II activates Ras in both cardiac myocytes and VSMCs.^{9 24} Aoki et al²⁵ have recently demonstrated that Ang II activates RhoA, which in turn mediates premyofibril formation as well as atrial natriuretic factor expression in cardiac myocytes. Schmitz et al⁵ have reported that Ang II activates protein-serine/threonine kinase PAK VSMCs. Since PAK interacts with and is activated by the GTP-bound form of Cdc42 and Rac, the Rho-family small GTP binding proteins, it is likely that Ang II activates Cdc42 and Rac. The kinase domain of the PAK is most closely related to yeast Ste20p, a known regulator of MAP kinase pathways. In fact, Schmitz et al have reported that PAK mediates Ang II–induced activation of JNK. Activation of each small GTP binding protein and respective downstream MAP kinase cascade seems to be mediated by a distinct tyrosine kinase. Src and Ca²⁺-dependent tyrosine kinase have been shown to mediate Ang II–induced Ras activation.^{9 24} Interestingly, Schmitz et al have suggested that a tyrosine kinase other than Src is involved in Ang II–induced PAK activation. The Ca²⁺-dependent tyrosine kinase activation is correlated with stimulation of the JNK and p70^S6K pathways but not with ERK or p90^RSK in liver GN4 cells.¹⁶ It has been suggested that tyrophostin-sensitive (unidentified) tyrosine kinases mediate activation of Rho by GPCRs.²⁶ Although Ras is constitutively in the cell membrane, Rho and Rac are predominantly cytosolic and must translocate to the cell membrane to be activated.²³ Therefore, the distinct subcellular localization seems to be well correlated with the hypothesis that the Ras and Rho families may be regulated by distinct tyrosine kinases.

Direct Association of Signaling Molecules With the AT₁ Receptor

The AT₁ receptor has been shown to directly associate with intracellular signaling molecules, such as Jak2, PTP-1D, and PLC-1. This ligand-dependent interaction requires a YIPP motif in the C-terminal domain of the AT₁ receptor.^{27 28} The interaction between the AT₁ receptor and intracellular signaling molecules creates membrane-delimited signal transduction complexes similar to those observed for receptor type tyrosine kinases. The AT₁ receptor associates with a Stat5 transcription factor after Ang II stimulation and apparently forms complexes with JAK2. The putative Stat5 binding motif (YXXL) has been found on intracellular loop 1 and on the carboxyl tail of the AT₁ receptor.²⁹ Small GTP binding proteins, ARF and RhoA, have been shown to interact with the amino acid sequence containing NPXXY (amino acids 298 to 302) in the seventh transmembrane domain of the AT₁ receptor in an Ang II–dependent manner in rat anterior pituitary cells. This direct interaction between the GPCR and ARF/RhoA seems to enhance coupling between the GPCR and phospholipase D.³⁰ Interestingly, the NPXXY motif is not found in all Gq-coupled receptors. Conversion of the DPXXY motif in another Gq-coupled gonadotropin-releasing hormone receptor to the NPXXY motif confers sensitivity to an inhibitor of ARF, suggesting that GPCRs utilize the sequence-specific cell signaling.³⁰ A similar direct interaction between GPCRs and the signaling molecule has been recently reported in the case of ß-adrenergic receptor and the Na⁺/H⁺ exchanger.³¹ The functional role of the direct interaction between the GPCR and signaling molecules, especially whether the interaction is the cause or the result of activation of the signaling molecules, remains to be determined. Nonetheless, these receptor sequence–specific cell signals initiated by GPCR stimulation confer more versatility to the GPCRs.

Unsolved Questions and Future Directions

The AT₁ receptor signaling demonstrates diverse cell-type specificity.^{32 33} Li et al²⁰ reported an interesting observation that PKC activation normally suppresses the tyrosine kinase (EGFR)-Ras-ERK pathway. However, once PKC is inactivated, this tyrosine kinase–dependent pathway completely compensates for ERK activation in liver GN4 cells.²⁰ If this observation is applicable to other cell types, the PKC dependence of ERK activation would be determined by the strength of the tyrosine kinase activities of the given cell types.

Another important issue is the unique Ang II–dependent cell signaling among G_q agonists. In cardiac myocytes, many Gq-agonists, including Ang II, phenylephrine, and endothelin-1, are known to induce cardiac hypertrophy.³⁴ These agonists seem to activate a similar set of signaling molecules. However, the profile of the signaling molecules activated by hypertrophic agonists has not been elucidated in detail. A recent report suggests that phenylephrine activates p38, resulting in an impressive hypertrophic response in cardiac myocytes.³⁵ It would be interesting to compare activation of p38 among hypertrophic agonists. If these receptors use sequence-specific signaling mechanisms as described above, sequence comparison among GPCRs would provide pertinent information.

Recent progress in the Ang II signaling field has made the linkage between AT₁ receptor and tyrosine kinase more clear and more significant compared with that a few years ago. We now understand in part why Ang II activates an array of signaling molecules as well as how Ang II can stimulate cell growth responses of the cardiovascular system almost as potently as agonists for the receptor-type tyrosine kinases do in other cell types. However, the mechanisms of many events proximal to the AT₁ receptor, such as tyrosine kinase activation, possible G protein–independent signaling mechanisms, and small GTP binding protein activation, remain unclear. Further investigation, including the structure-function analysis of the AT₁ receptor and identification of the receptor-associating protein, will be required to address such questions.

Selected Abbreviations and Acronyms

Ang II = angiotensin II AT1 = Ang II type 1 EGF = epidermal growth factor EGFR = EGF receptor ERK = extracellular signal–regulated kinase GPCR = G protein–coupled receptor JAK = Janus kinase JNK = c-Jun N-terminal kinase MAP kinase = mitogen-activated protein kinase PAK kinase = p21-activated kinase PKC = protein kinase C PLCß = phospholipase Cß VSMC = vascular smooth muscle cell

Footnotes

The opinions expressed in this article are not necessarily those of the editor or of the American Heart Association.

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