This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Eguchi, S. Articles by Hirata, Y. Search for Related Content PubMed PubMed Citation Articles by Eguchi, S. Articles by Hirata, Y.

(Hypertension. 1999;33:201-206.)
© 1999 American Heart Association, Inc.

Scientific Contributions

Involvement of PYK2 in Angiotensin II Signaling of Vascular Smooth Muscle Cells

Satoru Eguchi; Hiroaki Iwasaki; Tadashi Inagami; Kotaro Numaguchi; Tadashi Yamakawa; Evangeline D. Motley; Koji M. Owada; Fumiaki Marumo; Yukio Hirata

From the 2nd Department of Internal Medicine, Tokyo Medical and Dental University (S.E., H.I., F.M., Y.H.), Tokyo 113, Japan; Department of Biochemistry, Vanderbilt University School of Medicine (SE, T.I., K.N., T.Y.), Nashville, Tenn; Department of Anatomy and Physiology, Meharry Medical College (E.D.M), Nashville, Tenn; and Institute of Molecular and Cellular Biology for Pharmaceutical Sciences, Kyoto Pharmaceutical University (K.M.O.), Kyoto 607, Japan.

Correspondence to Satoru Eguchi, MD, PhD, the 2nd Department of Internal Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-Ku, Tokyo 113-8519, Japan. E-mail seguchi.med2{at}med.tmd.ac.jp

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Abstract—PYK2, a recently identified Ca²⁺-sensitive tyrosine kinase, has been implicated in extracellular signal-regulated kinase (ERK) activation via several G protein–coupled receptors. We have reported that angiotensin II (Ang II) induces Ca²⁺-dependent transactivation of the epidermal growth factor receptor (EGFR) which serves as a scaffold for preactivated c-Src and downstream adaptors (Shc/Grb2), leading to ERK activation in cultured rat vascular smooth muscle cells (VSMC). Herein we demonstrate the involvement of PYK2 in this cascade. Ang II rapidly induced tyrosine phosphorylation of PYK2, whose effect was completely inhibited by an AT₁ receptor antagonist and an intracellular Ca²⁺ chelator. A Ca²⁺ ionophore also induced PYK2 tyrosine phosphorylation to a level comparable with that by Ang II, whereas phorbol ester–induced phosphorylation was less than that by Ang II. Moreover, PYK2 formed a complex coprecipitable with catalytically active c-Src after Ang II stimulation. Although a selective EGFR kinase inhibitor completely abolished Ang II–induced recruitment of Grb2 to EGFR and markedly attenuated Ang II–induced ERK activation, it had no effect on Ang II–induced PYK2 tyrosine phosphorylation or its association with c-Src and Grb2. These data suggest that the AT₁ receptor uses Ca²⁺-dependent PYK2 to activate c-Src, thereby leading to EGFR transactivation, which preponderantly recruits Grb2 in rat VSMC.

Key Words: angiotensin II • receptors, angiotensin • proline-rich tyrosine kinase 2 • c-Src • epidermal growth factors • muscle, smooth, vascular • signal transduction

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Angiotensin II (Ang II), a dominant hemodynamic effector of the renin-angiotensin system, has been shown to promote hypertrophy or hyperplasia, or both, of vascular smooth muscle cells (VSMC),^{1 2 3} cardiac myocytes⁴ and cardiac fibroblasts.⁵ Ang II also enhances migration and extracellular matrix production of VSMC.⁶ Therefore, it is now widely believed that Ang II plays a key role in cardiovascular remodeling associated with hypertension, atherosclerosis, restenosis after vascular injury, heart failure, and even diabetes. This notion is supported by results of numerous in vivo experiments, as well as recent clinical trials, demonstrating multiple beneficial effects of ACE inhibitors and angiotensin type 1 receptor (AT₁R) antagonists in these disease states.^{7 8}

Thus, much progress has recently made to elucidate the signal transduction mechanisms leading to the growth-promoting effect through a G protein–coupled receptor (GPCR), AT₁R. It provides an exciting aspect that AT₁R shares typical signaling events with growth factor receptor such as tyrosine kinase activation and subsequent phosphorylation of the specific substrates accompanied by selective protein/protein interaction, resulting in activation of extracellular signal-regulated kinases (ERKs).^{6 9} We recently reported that Ang II induces Ca²⁺-dependent transactivation of the epidermal growth factor receptor (EGFR) that serves as a scaffold for preactivated c-Src kinase and downstream adaptor proteins, Shc/Grb2, leading to p21^ras/ERK activation in cultured rat VSMC.¹⁰ However, the mechanism linking AT₁R to the receptor tyrosine kinase EGFR has not been clear.

Recently, a novel nonreceptor tyrosine kinase with a high sequence homology to p125 focal adhesion kinase (FAK) was cloned by several groups and named proline-rich tyrosine kinase 2 (PYK2),¹¹ cell adhesion kinase ß,¹² related adhesion focal tyrosine kinase,¹³ and calcium-dependent tyrosine kinase.¹⁴ In PC12 cells, PYK2 mediates the recruitment of Grb2/Sos and subsequent p21^ras-dependent ERK activation in response to intracellular Ca²⁺ accumulation by a GPCR agonist, bradykinin, as well as membrane depolarization.¹¹ Moreover, PYK2 seems to operate these process in concert with c-Src.¹⁵ Recently, Ang II has also been shown to activate PYK2 in liver epithelial cells.¹⁴ The common feature that both EGFR and PYK2 signaling by GPCRs require intracellular Ca²⁺ elevation and c-Src activation prompted us to examine the possible involvement of PYK2 in the growth-promoting signal by Ang II in VSMC. In the present study, we assessed the contribution of PYK2 to the tyrosine kinase cascade operated through AT₁R that might exist upstream of the ERK activation in VSMC.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Materials
Ang II and phorbol-12-myristate-13-acetate (PMA) were obtained from Sigma. Recombinant human EGF was from Upstate Biotechnology. AG1478, A23187, and BAPTA-AM were from Calbiochem. An agarose-conjugated glutathione-S-transferase (GST)-Grb2 fusion protein and protein A/G-agarose were from Santa Cruz Biotechnology. CV11974 was a generous gift of Takeda Pharmaceutical Co. Anti-PYK2 polyclonal antibody (pAb) (06–559) and anti-phosphotyrosine monoclonal antibody (mAb) (4G10) were obtained from Upstate Biotechnology. Anti-PYK2 mAb (P47120) was from Transduction Laboratories. Anti-Src pAb (SRC2) and anti-EGF receptor pAb (1005) were from Santa Cruz Biotechnology. Anti-Src mAb (clone 327) was from Calbiochem. The mAb directed to Tyr530-dephosphorylated c-Src (clone 28) was prepared as described previously and selectively recognizes the active form of c-Src.¹⁶ Horseradish peroxidase-conjugated second antibodies were from Amersham.

Cell Culture
VSMC were prepared from the thoracic aorta of 12-week-old Sprague-Dawley rats (Charles River Breeding Laboratories) by the explant method and cultured in Dulbecco's modified Eagle's medium containing 10% FCS, penicillin, and streptomycin as previously described.¹⁷ Subcultured VSMC from passages 3 through 15 were used in the experiments. The predominant expression of AT₁R, but not of AT₂R, was confirmed by the binding study.¹⁸ Subconfluent cells were made quiescent under serum-free condition for 3 days.

Immunoprecipitation and Immunoblotting
Cells were lysed by adding ice-cold lysis buffer, pH 7.5, containing 50 mmol/L HEPES, 50 mmol/L NaCl, 1% Triton X-100, 10% glycerol, 1.5 mmol/L MgCl₂, 1 mmol/L EDTA, 10 mmol/L sodium pyrophosphate, 1 mmol/L Na₃VO₄, 100 mmol/L NaF, 30 mmol/L 2-(p-nitrophenyl)phosphate, 1 mmol/L PMSF, 10 mg/mL leupeptin, and 10 mg/mL aprotinin and centrifuged for 5 minutes at 14 000g. Supernatant was mixed with the antibodies for immunoprecipitation and rocked at 4°C for 2 to 16 hours, and then protein A/G Sepharose was added and incubated for an additional 2 to 16 hours. Immunoprecipitates were washed in lysis buffer, solubilized in Laemmli's sample buffer with 2-mercaptoethanol, resolved by SDS-PAGE, and transferred to nitrocellulose membrane. After blocking with 5% milk, the membrane was treated with a primary antibody, followed by a secondary antibody conjugated with horseradish peroxidase. Immunoreactive proteins were detected by enhanced chemiluminescence (Amersham) as described.¹⁰ For immunoblot analysis of Grb2-associable proteins, agarose-conjugated GST-Grb2 fusion protein was rocked with Triton X-100–treated cell lysate at 4°C for 2 to 16 hours and washed with lysis buffer. Bound proteins were solubilized, resolved by SDS-PAGE, and subjected to immunoblotting as described.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Ang II Activates PYK2 Through AT₁R
To assess whether Ang II activates PYK2 in VSMC, the effect of Ang II on phosphotyrosine content of PYK2 was examined. Treatment of quiescent rat VSMC with Ang II (10^-7 mol/L) markedly increased tyrosine-phosphorylated PYK2 as early as 2 minutes; neither phosphorylated band nor immunoprecipitated PYK2 was observed when normal rabbit IgG was used for the immunoprecipitation (Figure 1A). Pretreatment with 10^-5 mol/L CV11974, a selective AT₁R antagonist, completely blocked Ang II–induced tyrosine phosphorylation of PYK2 (Figure 1B). These data indicate that Ang II activates PYK2 via AT₁R in rat VSMC.

View larger version (28K): [in this window] [in a new window]   Figure 1. Ang II stimulates tyrosine phosphorylation of PYK2 through AT1R. A, VSMC were stimulated with Ang II (10-7 mol/L) for 2 minutes. After cell lysis, immunoprecipitation (IP) was performed with anti-PYK2 pAb or normal rabbit IgG. Precipitates were analyzed by immunoblotting (IB) with anti-phosphotyrosine (pTyr) mAb and anti-PYK2 mAb. B, VSMC pretreated with or without CV11974 (10-5 mol/L) for 30 minutes and then stimulated with Ang II (10-7 mol/L) for 2 minutes were subjected to IP and IB.

Calcium-Dependent PYK2 Activation by Ang II
PYK2 activation through GPCRs involves intracellular Ca²⁺ elevation and/or protein kinase C (PKC) activation in PC12 cells.¹¹ Stimulation of AT₁R activates phospholipase Cß to increase cytosolic free Ca²⁺ concentration ([Ca²⁺]_i) and activate PKC in VSMC.⁶ However, both p21^ras/ERK activation¹⁸ and EGFR transactivation¹⁰ via AT₁R are mainly mediated by an increase in [Ca²⁺]_i. To determine the Ca²⁺ dependence of PYK2 activation by Ang II in VSMC, the effect of an intracellular Ca²⁺ chelator (BAPTA-AM) was examined. Pretreatment with 10^-5 mol/L BAPTA-AM, but not with its solvent DMSO (0.1%), completely inhibited the Ang II–induced PYK2 phosphorylation (Figure 2A). The Ca²⁺ ionophore A23187 (10^-5 mol/L) also induced PYK2 tyrosine-phosphorylation comparable with that by 10^-7 mol/L Ang II, whereas a PKC activator, PMA (10^-6 mol/L), minimally induced PYK2 phosphorylation (Figure 2B). These data demonstrated that Ang II–induced PYK2 activation requires an increase in [Ca²⁺]_i rather than activation of PKC in rat VSMC.

View larger version (36K): [in this window] [in a new window]   Figure 2. Calcium-dependent PYK2 tyrosine phosphorylation by Ang II. A, VSMC were pretreated with 10-5 mol/L BAPTA-AM (BAPTA) or 0.1% dimethylsulfoxide (DMSO) for 30 minutes and then stimulated with Ang II (10-7 mol/L) for 2 minutes. Cell lysates were immunoprecipitated (IP) with anti-PYK2 pAb, followed by immunoblotting (IB) with anti-phosphotyrosine (pTyr) mAb and anti-PYK2 mAb. B, VSMC stimulated with Ang II (10-7 mol/L), A23187 (10-5 mol/L), or PMA (10-6 mol/L) for 2 minutes were subjected to IP and IB.

Association of PYK2 With c-Src by Ang II
The autophosphorylation of PYK2 at Tyr402 with the conserved YAEI sequence provides a selective binding site for the SH2 domains of Src family tyrosine kinase for its activation, which is essential for the PYK2-mediated ERK activation by several GPCR agonists.¹⁵ We¹⁰ and others¹⁹ have recently demonstrated that c-Src is involved in the Ang II–induced ERK activation in rat VSMC. To determine whether c-Src plays a role in PYK2 signaling activated by Ang II in VSMC, PYK2 immunoprecipitates after Ang II treatment were analyzed by immunoblotting with antibodies against active c-Src and phosphotyrosine. Ang II (10^-7 mol/L) initiated tyrosine phosphorylation of PYK2 as early as in 1 minute, which was sustained up to 5 minutes, with concomitant transient (1 to 2 minutes) association of PYK2 with catalytically active c-Src (Figure 3A). A 120-kDa tyrosine-phosphorylated protein was induced to associate with c-Src by Ang II, which comigrated with the band detected by the anti-PYK2 antibody (Figure 3B). A23187 (10^-5 mol/L) also increased the association of PYK2 with active c-Src (data not shown). These data provide evidence for the involvement of c-Src in PYK2 signaling initiated by AT₁R, presumably through an increase in [Ca²⁺]_i, a new finding to our knowledge.

View larger version (33K): [in this window] [in a new window]   Figure 3. Association of PYK2 with c-Src on Ang II stimulation. A, VSMC were stimulated with Ang II (10-7 mol/L) for indicated durations. Cell lysates were immunoprecipitated (IP) with anti-PYK2 pAb, followed by immunoblotting (IB) with anti-phosphotyrosine (pTyr) mAb, anti-PYK2 mAb, and anti-c-Src mAb (clone 28) by repeated reprobing. B, VSMC were stimulated with Ang II (10-7 mol/L) for 2 minutes. Cell lysates were immunoprecipitated (IP) with anti-c-Src pAb (SRC2), followed by immunoblotting (IB) with anti-PYK2 mAb, anti-phosphotyrosine (pTyr) mAb, and anti-c-Src mAb (clone 327) by repeated reprobing. Arrowheads indicate the position of PYK2.

Effect of EGFR Inhibition of PYK2 Signaling
We have recently shown that c-Src exists upstream of EGFR transactivation, which plays an essential role in the AT₁R-mediated Ca²⁺-dependent ERK activation in rat VSMC.¹⁰ Thus, it could be hypothesized that PYK2 may contribute to the EGFR transactivation through c-Src. To elucidate the hierarchical order of PYK2, c-Src, and EGFR, the effect was studied of a selective EGFR kinase inhibitor, AG1478, on the PYK2 phosphorylation and its association with c-Src. Neither phosphorylation of PYK2 nor its association with c-Src by Ang II (10^-7 mol/L) was inhibited by AG1478 at 2.5x10^-7 mol/L (Figure 4A), a concentration effective in inhibiting Ang II–induced ERK activation in rat VSMC.¹⁰ Furthermore, EGF (100 ng/mL) did not affect the phosphotyrosine content of PYK2 in rat VSMC (data not shown).

View larger version (41K): [in this window] [in a new window]   Figure 4. Effects of AG1478 on Ang II–induced association of PYK2 with c-Src and Grb2. A, VSMC were pretreated with 2.5x10-7 mol/L AG1478 or 0.1% dimethylsulfoxide (DMSO) for 30 minutes and then stimulated with Ang II (10-7 mol/L) for 2 minutes. Cell lysates were immunoprecipitated (IP) with anti-PYK2 pAb, followed by immunoblotting (IB) with anti-phosphotyrosine (pTyr) mAb, anti-PYK2 mAb, and anti-c-Src mAb (clone 28). B, VSMC were pretreated with 2.5x10-7 mol/L AG1478 or 0.1% dimethylsulfoxide (DMSO) for 30 minutes and then stimulated with Ang II (10-7 mol/L) for 2 minutes. After cell lysis, GST-Grb2 fusion protein was added. Proteins associated with the fusion protein were subjected to immunoblotting (IB) with anti-PYK2 mAb and anti-EGFR pAb.

The activated PYK2 has been shown to recruit Grb2 for the ERK activation in neuronal cells.¹¹ To elucidate whether similar mechanism is operated in VSMC after stimulation with Ang II, the lysates of VSMC stimulated by Ang II (10^-7 mol/L) with or without pretreatment of AG1478 (2.5x10^-7 mol/L) for 30 minutes were coprecipitated with GST-Grb2-fusion protein, followed by immunoblotting with antibodies against EGFR or PYK2. Ang II increased the amounts of PYK2 coprecipitable with the fusion protein regardless of the presence of AG1478, whereas AG1478 completely inhibited Ang II–induced association of EGFR with the fusion protein (Figure 4B). Thus, activation of PYK2, as well as its association with c-Src and Grb2 in response to Ang II, occurs independent of EGFR kinase activity, suggesting that PYK2 may be located upstream of and/or in parallel with the EGFR in VSMC.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
A growing body of evidence indicates that the growth-promoting effect by Ang II is mediated by activation of several protein tyrosine kinases.^{6 9} Earlier studies from our laboratory indicated that a Ca²⁺-dependent tyrosine kinase or kinases may transmit AT₁R signal to the ERK cascade in rat VSMC.¹⁸ Subsequently, we have shown EGFR as such a tyrosine kinase.¹⁰ Here, we further identified and characterized another AT₁R-responsive Ca²⁺-dependent tyrosine kinase as PYK2 in rat VSMC.

PYK2 has been shown to be regulated by Ca²⁺ signal in PC12 cells¹¹ and constitutes a major Ca²⁺-dependent tyrosine kinase in Ang II–stimulated liver epithelial cells.¹⁴ The Ca²⁺-dependency of the Ang II–induced PYK2 activation as demonstrated in this study is consistent with a recent report showing that Ang II– and platelet-derived growth factor–stimulated PYK2 activation was inhibitable with the intracellular Ca²⁺ chelator in rat VSMC,²⁰ whereas the importance of PKC was also suggested. However, the present results appear to demonstrate that PYK2 phosphorylation by PMA is much weaker than those by Ang II and a Ca²⁺ ionophore, suggesting a preferential role of calcium to PKC in regulation of PYK2 in VSMC. Because PYK2, which lacks calmodulin-binding motif, cannot be activated by either Ca²⁺ or calmodulin in vitro,¹¹ the mechanism by which Ca²⁺ signal activates PYK2 remains to be determined.

Src family tyrosine kinase has been implicated in the ERK activation by various agonists for GPCRs, including AT₁R.^{21 22 23} Recently, it has been reported that both G_q and G_i agonists, such as bradykinin and lysophosphatidic acid, respectively, induced association of PYK2 with c-Src through binding of autophosphorylated Tyr402 of PYK2 to the SH2 domain of c-Src, thereby leading to c-Src activation.¹⁵ The activated c-Src could further phosphorylate PYK2 at Tyr881 followed by the LNV sequence and an adaptor protein Shc, thereby recruiting the Grb2/Sos complex. These events are believed to be essential for the ERK activation by GPCR agonists in PC12 cells.¹⁵ The calcium-dependent PYK2/c-Src activation has also been shown to bridge both G_i- and G_q-coupled receptors to the ERK activation in HEK 293 cells.²⁴ In rat VSMC, we have recently shown that Ang II increased transient association of active c-Src with Shc that is contingent on Shc phosphorylation.¹⁰ In the present study, we further demonstrated that PYK2 formed a complex with an active c-Src and Grb2 on Ang II stimulation. Therefore, it is reasonable to speculate that PYK2 may contribute to the Ang II–induced ERK activation in concert with Src family tyrosine kinase and adaptors (Shc and Grb2) in cells where AT₁R promotes cell growth, such as in VSMC.

In addition to PYK2 and c-Src, combination of multiple tyrosine kinases appears to be involved in the ERK activation by GPCR agonists depending on cell type. For example, the G_q-coupled ERK activation requires Csk, Lyn, and Syk, whereas the G_i-coupled activation requires Btk and Syk in avian lymphoma cells.²⁵ We and others have recently shown that c-Src acts upstream of EGFR transactivation to feed into the ERK cascade through G_q-coupled AT₁R in rat VSMC¹⁰ and G_i-coupled lysophosphatidic acid and _2A-adrenergic receptors in COS-7 cells,²⁶ respectively. Interestingly, not only PYK2 and c-Src,¹⁵ but also EGFR,²⁷ appear to be essential for the Ca²⁺-dependent ERK activation by GPCR agonists in PC12 cells. Thus, the Ang II–induced Ca²⁺-dependent PYK2 activation accompanied by its interaction with c-Src as demonstrated in this study and the Ang II–induced association of c-Src with EGFR as demonstrated in our previous study¹⁰ strongly suggest that PYK2 function is mainly located upstream of the AT₁R-mediated EGFR transactivation. This is consistent with the present observation that neither PYK2 phosphorylation nor its association with active c-Src requires EGFR kinase activity after Ang II stimulation.

Alternatively, PYK2 could function in parallel with EGFR to feed into the ERK cascade because Ang II–induced association of Grb2 with PYK2 occurred even when the association of Grb2 with EGFR was completely blocked by AG1478. In liver epithelial cells, Ca²⁺- and PKC-dependent PYK2 activation by Ang II was reported,¹⁴ whereas the Ang II–induced EGFR transactivation appeared to be driven only when cellular PKC was depleted.²⁸ However, we have recently shown that AG1478 markedly inhibited the Ang II–induced ERK activation.¹⁰ Taken together, we submit that the recruitment of Grb2 by PYK2 contributes little, if any, to the ERK activation through AT₁R and that the ERK activation by Ang II appears to be preferentially mediated by the recruitment of Grb2 to the EGFR in VSMC. A possible involvement of PYK2 in signal transduction of Ang II–induced ERK activation is illustrated in Figure 5.

View larger version (20K): [in this window] [in a new window]   Figure 5. Possible involvement of PYK2 in signal transduction of VSMC operated through AT1R. Ang II induces ERK cascade (Ras, Raf, MEK, ERK) through adaptors (Shc and Grb2) and Sos recruited through EGFR that is transphosphorylated by c-Src. The c-Src activation is mainly mediated through PYK2, which senses intracellular Ca2+ elevation by Gq/phospholipase C–coupled AT1R. PYK2 may also contributes to the direct recruitment of Grb2/Sos complex for ERK activation, although possibly constituting a minor component.

PYK2 may account for other signaling pathways than the ERK cascade by AT₁R in VSMC. PYK2 is involved in c-Jun amino-terminal kinase (JNK) activation induced by tumor necrosis factor-, ultraviolet irradiation, and osmotic shock.²⁹ It has been shown that PYK2 activation is correlated with JNK activation¹⁴ and p70 ribosomal S6 kinase activation, but not ERK activation,³⁰ in Ang II–stimulated rat liver epithelial cells. In addition, PYK2 has a "focal adhesion-targeting domain" homologous to that of FAK.¹³ In fact, PYK2 has been shown to be tyrosine-phosphorylated after ß₁-integrin stimulation³¹ and to be associated with a cytoskeletal protein, paxillin.³² In this regard, it has recently been reported that paxillin is tyrosine-phosphorylated by and associates with PYK2 in Ang II–stimulated rat liver epithelial cells.³³ Because these tyrosine kinases (PYK2, c-Src, EGFR) may phosphorylate each other as well as respective specific substrates and recruit additional signaling molecules, several signaling events branching at the level of these kinases will account for diverse functions of the AT₁R in a tissue- and cell type–specific manner.

In conclusion, we have demonstrated that Ang II induces a Ca²⁺-dependent PYK2 activation and its interaction with c-Src and Grb2 in rat VSMC. Further elucidation of cross-talk between AT₁R and protein tyrosine kinases, as well as their downstream signals, should unravel the exact role of Ang II in the mechanism of vascular remodeling under pathological states, such as in hypertension, atherosclerosis, and restenosis after angioplasty.

	Acknowledgments

 
This study was supported in part by Grants-in-Aid from the Ministry of Education, Science, and Culture, the Ministry of Health and Welfare of Japan, and the Tokyo Hypertension Conference and by National Institutes of Health Grants HL-58205, HL-35323, HL-03320, and DK-20593.

Received September 16, 1998; first decision October 14, 1998; accepted October 28, 1998.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Geisterfer AA, Peach MJ, Owens GK. Angiotensin II induces hypertrophy, not hyperplasia, of cultured rat aortic smooth muscle cells. Circ Res. 1988;62:749–756.[Abstract/Free Full Text]

2. Gibbons GH, Pratt RE, Dzau VJ. Vascular smooth muscle cell hypertrophy vs hyperplasia: autocrine transforming growth factor-ß1 expression determines growth response to angiotensin II. J Clin Invest. 1992;90:456–461.

3. Weber H, Taylor DS, Molloy CJ. Angiotensin II induces delayed mitogenesis and cellular proliferation in rat aortic smooth muscle cells: correlation with the expression of specific endogenous growth factors and reversal by suramin. J Clin Invest. 1994;93:788–798.

4. Sadoshima J, Izumo S. Molecular characterization of angiotensin II-induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts: critical role of the AT1 receptor subtype. Circ Res. 1993;73:413–423.[Abstract/Free Full Text]

5. Schorb W, Booz GW, Dostal DE, Conrad KM, Chang KC, Baker KM. Angiotensin II is mitogenic in neonatal rat cardiac fibroblasts. Circ Res. 1993;72:1245–1254.[Abstract/Free Full Text]

6. Griendling KK, Ushio FM, Lassegue B, Alexander RW. Angiotensin II signaling in vascular smooth muscle: new concepts. Hypertension. 1997;29:366–373.[Abstract/Free Full Text]

7. Goodfriend TL, Elliott ME, Catt KJ. Angiotensin receptors and their antagonists. N Engl J Med. 1996;334:1649–1654.[Free Full Text]

8. Brown NJ, Vaughan DE. Angiotensin-converting enzyme inhibitors. Circulation. 1998;97:1411–1420.[Abstract/Free Full Text]

9. Berk BC, Corson MA. Angiotensin II signal transduction in vascular smooth muscle: role of tyrosine kinases. Circ Res. 1997;80:607–616.[Abstract/Free Full Text]

10. Eguchi S, Numaguchi K, Iwasaki H, Matsumoto T, Yamakawa T, Utsunomiya H, Motley ED, Kawakatsu H, Owada KM, Hirata Y, Marumo F, Inagami T. Calcium-dependent epidermal growth factor receptor transactivation mediates the angiotensin II-induced mitogen-activated protein kinase activation in vascular smooth muscle cells. J Biol Chem. 1998;273:8890–8896.[Abstract/Free Full Text]

11. Lev S, Moreno H, Martinez R, Canoll P, Peles E, Musacchio JM, Plowman GD, Rudy B, Schlessinger J. Protein tyrosine kinase PYK2 involved in Ca²⁺-induced regulation of ion channel and MAP kinase functions. Nature. 1995;376:737–745.[Medline] [Order article via Infotrieve]

12. Sasaki H, Nagura K, Ishino M, Tobioka H, Kotani K, Sasaki T. Cloning and characterization of cell adhesion kinase ß, a novel protein-tyrosine kinase of the focal adhesion kinase subfamily. J Biol Chem. 1995;270:21206–21219.[Abstract/Free Full Text]

13. Avraham S, London R, Fu Y, Ota S, Hiregowdara D, Li J, Jiang S, Pasztor LM, White RA, Groopman JE, Avraham H. Identification and characterization of a novel related adhesion focal tyrosine kinase (RAFTK) from megakaryocytes and brain. J Biol Chem. 1995;270:27742–27751.[Abstract/Free Full Text]

14. Yu H, Li X, Marchetto GS, Dy R, Hunter D, Calvo B, Dawson TL, Wilm M, Anderegg RJ, Graves LM, Earp HS. Activation of a novel calcium-dependent protein-tyrosine kinase: correlation with c-Jun N-terminal kinase but not mitogen-activated protein kinase activation. J Biol Chem. 1996;271:29993–29998.[Abstract/Free Full Text]

15. Dikic I, Tokiwa G, Lev S, Courtneidge SA, Schlessinger J. A role for Pyk2 and Src in linking G-protein-coupled receptors with MAP kinase activation. Nature. 1996;383:547–550.[Medline] [Order article via Infotrieve]

16. Kawakatsu H, Sakai T, Takagaki Y, Shinoda Y, Saito M, Owada MK, Yano J. A new monoclonal antibody which selectively recognizes the active form of Src tyrosine kinase. J Biol Chem. 1996;271:5680–5685.[Abstract/Free Full Text]

17. Eguchi S, Hirata Y, Imai T, Kanno K, Marumo F. Phenotypic change of endothelin receptor subtype in cultured rat vascular smooth muscle cells. Endocrinology. 1994;134:222–228.[Abstract/Free Full Text]

18. Eguchi S, Matsumoto T, Motley ED, Utsunomiya H, Inagami T. Identification of an essential signaling cascade for mitogen-activated protein kinase activation by angiotensin II in cultured rat vascular smooth muscle cells: possible requirement of Gq-mediated p21^ras activation coupled to a Ca²⁺/calmodulin-sensitive tyrosine kinase. J Biol Chem. 1996;271:14169–14175.[Abstract/Free Full Text]

19. Ishida M, Ishida T, Thomas SM, Berk BC. Activation of extracellular signal-regulated kinases (ERK1/2) by angiotensin II is dependent on c-Src in vascular smooth muscle cells. Circ Res. 1998;82:7–12.[Abstract/Free Full Text]

20. Brinson AE, Harding T, Diliberto PA, He Y, Li X, Hunter D, Herman B, Earp HS, Graves LM. Regulation of a calcium-dependent tyrosine kinase in vascular smooth muscle cells by angiotensin II and platelet-derived growth factor: dependence on calcium and the actin cytoskeleton. J Biol Chem. 1998;273:1711–1718.[Abstract/Free Full Text]

21. Luttrell LM, Hawes BE, van Biesen T, Luttrell DK, Lansing TJ, Lefkowitz RJ. Role of c-Src tyrosine kinase in G protein-coupled receptor- and Gß subunit-mediated activation of mitogen-activated protein kinases. J Biol Chem. 1996;271:19443–19450.[Abstract/Free Full Text]

22. Wan Y, Kurosaki T, Huang XY. Tyrosine kinases in activation of the MAP kinase cascade by G-protein-coupled receptors. Nature. 1996;380:541–544.[Medline] [Order article via Infotrieve]

23. Sadoshima J, Izumo S. The heterotrimeric Gq protein-coupled angiotensin II receptor activates p21 ras via the tyrosine kinase-Shc-Grb2-Sos pathway in cardiac myocytes. EMBO J. 1996;15:775–787.[Medline] [Order article via Infotrieve]

24. Della Rocca GJ, van Biesen T, Daaka Y, Luttrell DK, Luttrell LM, Lefkowitz RJ. Ras-dependent mitogen-activated protein kinase activation by G protein-coupled receptors: convergence of Gi- and Gq-mediated pathways on calcium/calmodulin, Pyk2, and Src kinase. J Biol Chem. 1997;272:19125–32.[Abstract/Free Full Text]

25. Wan Y, Bence K, Hata A, Kurosaki T, Veillette A, Huang XY. Genetic evidence for a tyrosine kinase cascade preceding the mitogen-activated protein kinase cascade in vertebrate G protein signaling. J Biol Chem. 1997;272:17209–17215.[Abstract/Free Full Text]

26. Luttrell LM, Della Rocca GJ, van Biesen T, Luttrell DK, Lefkowitz RJ. Gß subunits mediate Src-dependent phosphorylation of the epidermal growth factor receptor: a scaffold for G protein-coupled receptor-mediated Ras activation. J Biol Chem. 1997;272:4637–4644.[Abstract/Free Full Text]

27. Zwick E, Daub H, Aoki N, Yamaguchi AY, Tinhofer I, Maly K, Ullrich A. Critical role of calcium-dependent epidermal growth factor receptor transactivation in PC12 cell membrane depolarization and bradykinin signaling. J Biol Chem. 1997;272:24767–24770.[Abstract/Free Full Text]

28. Li X, Lee JW, Graves LM, Earp HS. Angiotensin II stimulates ERK via two pathways in epithelial cells: protein kinase C suppresses a G-protein coupled receptor-EGF receptor transactivation pathway. EMBO J. 1998;17:2574–2583.[Medline] [Order article via Infotrieve]

29. Tokiwa G, Dikic I, Lev S, Schlessinger J. Activation of Pyk2 by stress signals and coupling with JNK signaling pathway. Science. 1996;273:792–794.[Abstract]

30. Graves LM, He Y, Lambert J, Hunter D, Li X, Earp HS. An intracellular calcium signal activates p70 but not p90 ribosomal S6 kinase in liver epithelial cells. J Biol Chem. 1997;272:1920–1928.[Abstract/Free Full Text]

31. Astier A, Avraham H, Manie SN, Groopman J, Canty T, Avraham S, Freedman AS. The related adhesion focal tyrosine kinase is tyrosine-phosphorylated after ß1-integrin stimulation in B cells and binds to p130^cas. J Biol Chem. 1997;272:228–232.[Abstract/Free Full Text]

32. Avraham S, Avraham H. Characterization of the novel focal adhesion kinase RAFTK in hematopoietic cells. Leukemia Lymphoma. 1997;27:247–256.

33. Li X, Earp HS. Paxillin is tyrosine-phosphorylated by and preferentially associates with the calcium-dependent tyrosine kinase in rat liver epithelial cells. J Biol Chem. 1997;272:14341–14348.[Abstract/Free Full Text]

This article has been cited by other articles:

				D. Schauwienold, A. P. Sastre, N. Genzel, M. Schaefer, and H. P. Reusch The Transactivated Epidermal Growth Factor Receptor Recruits Pyk2 to Regulate Src Kinase Activity J. Biol. Chem., October 10, 2008; 283(41): 27748 - 27756. [Abstract] [Full Text] [PDF]

				H. Ohtsu, S. Higuchi, H. Shirai, K. Eguchi, H. Suzuki, A. Hinoki, E. Brailoiu, A. D. Eckhart, G. D. Frank, and S. Eguchi Central Role of Gq in the Hypertrophic Signal Transduction of Angiotensin II in Vascular Smooth Muscle Cells Endocrinology, July 1, 2008; 149(7): 3569 - 3575. [Abstract] [Full Text] [PDF]

				P. K. Mehta and K. K. Griendling Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system Am J Physiol Cell Physiol, January 1, 2007; 292(1): C82 - C97. [Abstract] [Full Text] [PDF]

				A. D. Burdick, I. D. Ivnitski-Steele, F. T. Lauer, and S. W. Burchiel PYK2 mediates anti-apoptotic AKT signaling in response to benzo[a]pyrene diol epoxide in mammary epithelial cells Carcinogenesis, November 1, 2006; 27(11): 2331 - 2340. [Abstract] [Full Text] [PDF]

				M. Ushio-Fukai and R. W. Alexander Caveolin-Dependent Angiotensin II Type 1 Receptor Signaling in Vascular Smooth Muscle Hypertension, November 1, 2006; 48(5): 797 - 803. [Full Text] [PDF]

				D. Chansel, M. Ciroldi, S. Vandermeersch, L. F Jackson, A.-M. Gomez, D. Henrion, D. C. Lee, T. M. Coffman, S. Richard, J.-C. Dussaule, et al. Heparin binding EGF is necessary for vasospastic response to endothelin FASEB J, September 1, 2006; 20(11): 1936 - 1938. [Abstract] [Full Text] [PDF]

				A. N. Lyle and K. K. Griendling Modulation of vascular smooth muscle signaling by reactive oxygen species. Physiology, August 1, 2006; 21: 269 - 280. [Abstract] [Full Text] [PDF]

				E. A. Woolfolk, S. Eguchi, H. Ohtsu, H. Nakashima, H. Ueno, W. T. Gerthoffer, and E. D. Motley Angiotensin II-induced activation of p21-activated kinase 1 requires Ca2+ and protein kinase C{delta} in vascular smooth muscle cells Am J Physiol Cell Physiol, November 1, 2005; 289(5): C1286 - C1294. [Abstract] [Full Text] [PDF]

				U. G. B. Haider, T. U. Roos, M. I. Kontaridis, B. G. Neel, D. Sorescu, K. K. Griendling, A. M. Vollmar, and V. M. Dirsch Resveratrol Inhibits Angiotensin II- and Epidermal Growth Factor-Mediated Akt Activation: Role of Gab1 and Shp2 Mol. Pharmacol., July 1, 2005; 68(1): 41 - 48. [Abstract] [Full Text] [PDF]

				Q. Che and P. K. Carmines Src family kinase involvement in rat preglomerular microvascular contractile and [Ca2+]i responses to ANG II Am J Physiol Renal Physiol, April 1, 2005; 288(4): F658 - F664. [Abstract] [Full Text] [PDF]

				S. Amos, P. M. Martin, G. A. Polar, S. J. Parsons, and I. M. Hussaini Phorbol 12-Myristate 13-Acetate Induces Epidermal Growth Factor Receptor Transactivation via Protein Kinase C{delta}/c-Src Pathways in Glioblastoma Cells J. Biol. Chem., March 4, 2005; 280(9): 7729 - 7738. [Abstract] [Full Text] [PDF]

				X. Li, K. M. Lerea, J. Li, and S. C. Olson Src Kinase Mediates Angiotensin II-Dependent Increase in Pulmonary Endothelial Nitric Oxide Synthase Am. J. Respir. Cell Mol. Biol., September 1, 2004; 31(3): 365 - 372. [Abstract] [Full Text] [PDF]

				T. Yoshimoto, N. Fukai, R. Sato, T. Sugiyama, N. Ozawa, M. Shichiri, and Y. Hirata Antioxidant Effect of Adrenomedullin on Angiotensin II-Induced Reactive Oxygen Species Generation in Vascular Smooth Muscle Cells Endocrinology, July 1, 2004; 145(7): 3331 - 3337. [Abstract] [Full Text] [PDF]

				R. Ginnan, P. J. Pfleiderer, K. Pumiglia, and H. A. Singer PKC-{delta} and CaMKII-{delta}2 mediate ATP-dependent activation of ERK1/2 in vascular smooth muscle Am J Physiol Cell Physiol, June 1, 2004; 286(6): C1281 - C1289. [Abstract] [Full Text] [PDF]

				K. Natarajan, G. Yin, and B. C. Berk Scaffolds Direct Src-Specific Signaling in Response to Angiotensin II: New Roles for Cas and GIT1 Mol. Pharmacol., April 1, 2004; 65(4): 822 - 825. [Full Text]

				Y. V. Mukhin, M. N. Garnovskaya, M. E. Ullian, and J. R. Raymond ERK Is Regulated by Sodium-Proton Exchanger in Rat Aortic Vascular Smooth Muscle Cells J. Biol. Chem., January 16, 2004; 279(3): 1845 - 1852. [Abstract] [Full Text] [PDF]

				G. Yin, J. Haendeler, C. Yan, and B. C. Berk GIT1 Functions as a Scaffold for MEK1-Extracellular Signal-Regulated Kinase 1 and 2 Activation by Angiotensin II and Epidermal Growth Factor Mol. Cell. Biol., January 15, 2004; 24(2): 875 - 885. [Abstract] [Full Text] [PDF]

				J. Haendeler, G. Yin, Y. Hojo, Y. Saito, M. Melaragno, C. Yan, V. K. Sharma, M. Heller, R. Aebersold, and B. C. Berk GIT1 Mediates Src-dependent Activation of Phospholipase C{gamma} by Angiotensin II and Epidermal Growth Factor J. Biol. Chem., December 12, 2003; 278(50): 49936 - 49944. [Abstract] [Full Text] [PDF]

				P. Rocic, H. Jo, and P. A. Lucchesi A role for PYK2 in ANG II-dependent regulation of the PHAS-1-eIF4E complex by multiple signaling cascades in vascular smooth muscle Am J Physiol Cell Physiol, December 1, 2003; 285(6): C1437 - C1444. [Abstract] [Full Text] [PDF]

				A. Kawakami, A. Tanaka, T. Chiba, K. Nakajima, K. Shimokado, and M. Yoshida Remnant Lipoprotein-Induced Smooth Muscle Cell Proliferation Involves Epidermal Growth Factor Receptor Transactivation Circulation, November 25, 2003; 108(21): 2679 - 2688. [Abstract] [Full Text] [PDF]

				Y. Taniyama, D. S. Weber, P. Rocic, L. Hilenski, M. L. Akers, J. Park, B. A. Hemmings, R. W. Alexander, and K. K. Griendling Pyk2- and Src-Dependent Tyrosine Phosphorylation of PDK1 Regulates Focal Adhesions Mol. Cell. Biol., November 15, 2003; 23(22): 8019 - 8029. [Abstract] [Full Text] [PDF]

				A. Konishi and B. C. Berk Epidermal Growth Factor Receptor Transactivation Is Regulated by Glucose in Vascular Smooth Muscle Cells J. Biol. Chem., September 12, 2003; 278(37): 35049 - 35056. [Abstract] [Full Text] [PDF]

				C. Suarez, G. Diaz-Torga, A. Gonzalez-Iglesias, J. Vela, A. Mladovan, A. Baldi, and D. Becu-Villalobos Angiotensin II phosphorylation of extracellular signal-regulated kinases in rat anterior pituitary cells Am J Physiol Endocrinol Metab, September 1, 2003; 285(3): E645 - E653. [Abstract] [Full Text] [PDF]

				H. Iwasaki, T. Yoshimoto, T. Sugiyama, and Y. Hirata Activation of Cell Adhesion Kinase {beta} by Mechanical Stretch in Vascular Smooth Muscle Cells Endocrinology, June 1, 2003; 144(6): 2304 - 2310. [Abstract] [Full Text] [PDF]

				Y. E.G. Eskildsen-Helmond and M. J. Mulvany Pressure-Induced Activation of Extracellular Signal-Regulated Kinase 1/2 in Small Arteries Hypertension, April 1, 2003; 41(4): 891 - 897. [Abstract] [Full Text] [PDF]

				K. Seta and J. Sadoshima Phosphorylation of Tyrosine 319 of the Angiotensin II Type 1 Receptor Mediates Angiotensin II-induced Trans-activation of the Epidermal Growth Factor Receptor J. Biol. Chem., March 7, 2003; 278(11): 9019 - 9026. [Abstract] [Full Text] [PDF]

				G. D. Frank, M. Mifune, T. Inagami, M. Ohba, T. Sasaki, S. Higashiyama, P. J. Dempsey, and S. Eguchi Distinct Mechanisms of Receptor and Nonreceptor Tyrosine Kinase Activation by Reactive Oxygen Species in Vascular Smooth Muscle Cells: Role of Metalloprotease and Protein Kinase C-{delta} Mol. Cell. Biol., March 1, 2003; 23(5): 1581 - 1589. [Abstract] [Full Text] [PDF]

				Y. V. Mukhin, E. A. Garnovsky, M. E. Ullian, and M. N. Garnovskaya Bradykinin B2 Receptor Activates Extracellular Signal-Regulated Protein Kinase in mIMCD-3 Cells via Epidermal Growth Factor Receptor Transactivation J. Pharmacol. Exp. Ther., March 1, 2003; 304(3): 968 - 977. [Abstract] [Full Text] [PDF]

				B. H. Shah, J.-W. Soh, and K. J. Catt Dependence of Gonadotropin-releasing Hormone-induced Neuronal MAPK Signaling on Epidermal Growth Factor Receptor Transactivation J. Biol. Chem., January 24, 2003; 278(5): 2866 - 2875. [Abstract] [Full Text] [PDF]

				J. Buteau, S. Foisy, E. Joly, and M. Prentki Glucagon-Like Peptide 1 Induces Pancreatic {beta}-Cell Proliferation Via Transactivation of the Epidermal Growth Factor Receptor Diabetes, January 1, 2003; 52(1): 124 - 132. [Abstract] [Full Text] [PDF]

				L.-K. Tai, M. Okuda, J.-i. Abe, C. Yan, and B. C. Berk Fluid Shear Stress Activates Proline-Rich Tyrosine Kinase via Reactive Oxygen Species-Dependent Pathway Arterioscler Thromb Vasc Biol, November 1, 2002; 22(11): 1790 - 1796. [Abstract] [Full Text] [PDF]

				J. D. Curlewis, S. P. Tam, P. Lau, D. H. L. Kusters, J. L. Barclay, S. T. Anderson, and M. J. Waters A Prostaglandin F2{alpha} Analog Induces Suppressors of Cytokine Signaling-3 Expression in the Corpus Luteum of the Pregnant Rat: A Potential New Mechanism in Luteolysis Endocrinology, October 1, 2002; 143(10): 3984 - 3993. [Abstract] [Full Text] [PDF]

				J. N. McLaughlin, C. D. Thulin, S. M. Bray, M. M. Martin, T. S. Elton, and B. M. Willardson Regulation of Angiotensin II-induced G Protein Signaling by Phosducin-like Protein J. Biol. Chem., September 13, 2002; 277(38): 34885 - 34895. [Abstract] [Full Text] [PDF]

				J. Kim, A. D. Eckhart, S. Eguchi, and W. J. Koch beta -Adrenergic Receptor-mediated DNA Synthesis in Cardiac Fibroblasts Is Dependent on Transactivation of the Epidermal Growth Factor Receptor and Subsequent Activation of Extracellular Signal-regulated Kinases J. Biol. Chem., August 23, 2002; 277(35): 32116 - 32123. [Abstract] [Full Text] [PDF]

				B. H. Shah, J. Alberto Olivares-Reyes, A. Yesilkaya, and K. J. Catt Independence of Angiotensin II-Induced MAP Kinase Activation from Angiotensin Type 1 Receptor Internalization in Clone 9 Hepatocytes Mol. Endocrinol., March 1, 2002; 16(3): 610 - 620. [Abstract] [Full Text] [PDF]

				K. L. Byron and P. A. Lucchesi Signal Transduction of Physiological Concentrations of Vasopressin in A7r5 Vascular Smooth Muscle Cells. A ROLE FOR PYK2 AND TYROSINE PHOSPHORYLATION OF K+ CHANNELS IN THE STIMULATION OF Ca2+ SPIKING J. Biol. Chem., February 22, 2002; 277(9): 7298 - 7307. [Abstract] [Full Text] [PDF]

				G. D. Frank, S. Saito, E. D. Motley, T. Sasaki, M. Ohba, T. Kuroki, T. Inagami, and S. Eguchi Requirement of Ca2+ and PKC{delta} for Janus Kinase 2 Activation by Angiotensin II: Involvement of PYK2 Mol. Endocrinol., February 1, 2002; 16(2): 367 - 377. [Abstract] [Full Text] [PDF]

				B. H. Shah and K. J. Catt Calcium-Independent Activation of Extracellularly Regulated Kinases 1 and 2 by Angiotensin II in Hepatic C9 Cells: Roles of Protein Kinase Cdelta , Src/Proline-Rich Tyrosine Kinase 2, and Epidermal Growth Factor Receptor trans-Activation Mol. Pharmacol., February 1, 2002; 61(2): 343 - 351. [Abstract] [Full Text] [PDF]

				R. Shimizu-Hirota, H. Sasamura, M. Mifune, H. Nakaya, M. Kuroda, M. Hayashi, and T. Saruta Regulation of Vascular Proteoglycan Synthesis by Angiotensin II Type 1 and Type 2 Receptors J. Am. Soc. Nephrol., December 1, 2001; 12(12): 2609 - 2615. [Abstract] [Full Text] [PDF]

				M. Igarashi, A. Hirata, H. Yamaguchi, H. Tsuchiya, H. Ohnuma, M. Tominaga, M. Daimon, and T. Kato Candesartan Inhibits Carotid Intimal Thickening and Ameliorates Insulin Resistance in Balloon-Injured Diabetic Rats Hypertension, December 1, 2001; 38(6): 1255 - 1259. [Abstract] [Full Text] [PDF]

				M. Yoshizumi, K. Tsuchiya, K. Kirima, M. Kyaw, Y. Suzaki, and T. Tamaki Quercetin Inhibits Shc- and Phosphatidylinositol 3-Kinase-Mediated c-Jun N-Terminal Kinase Activation by Angiotensin II in Cultured Rat Aortic Smooth Muscle Cells Mol. Pharmacol., October 1, 2001; 60(4): 656 - 665. [Abstract] [Full Text] [PDF]

				G. Petrescu, M. Costuleanu, S. M. Slatineanu, N. Costuleanu, L. Foia, and A. Costuleanu Contractile effects of angiotensin peptides in rat aorta are differentially dependent on tyrosine kinase activity Journal of Renin-Angiotensin-Aldosterone System, September 1, 2001; 2(3): 180 - 187. [Abstract] [PDF]

				B. C. Berk Vascular Smooth Muscle Growth: Autocrine Growth Mechanisms Physiol Rev, July 1, 2001; 81(3): 999 - 1030. [Abstract] [Full Text] [PDF]

				M. El Mabrouk, R. M. Touyz, and E. L. Schiffrin Differential ANG II-induced growth activation pathways in mesenteric artery smooth muscle cells from SHR Am J Physiol Heart Circ Physiol, July 1, 2001; 281(1): H30 - H39. [Abstract] [Full Text] [PDF]

				P. M. Ghosh, M. Mikhailova, R. Bedolla, and J. I. Kreisberg Arginine vasopressin stimulates mesangial cell proliferation by activating the epidermal growth factor receptor Am J Physiol Renal Physiol, June 1, 2001; 280(6): F972 - F979. [Abstract] [Full Text] [PDF]

				K. Takeda, T. Ichiki, T. Tokunou, N. Iino, S. Fujii, A. Kitabatake, H. Shimokawa, and A. Takeshita Critical Role of Rho-Kinase and MEK/ERK Pathways for Angiotensin II-Induced Plasminogen Activator Inhibitor Type-1 Gene Expression Arterioscler Thromb Vasc Biol, May 1, 2001; 21(5): 868 - 873. [Abstract] [Full Text] [PDF]

				G. A. Stouffer, C. Patterson, N. Madamanchi, and M. S. Runge Role of Reactive Oxygen Species in Angiotensin II Signaling : The Plot Thickens Arterioscler Thromb Vasc Biol, April 1, 2001; 21(4): 471 - 472. [Full Text] [PDF]

				M. Ushio-Fukai, K. K. Griendling, P. L. Becker, L. Hilenski, S. Halleran, and R. W. Alexander Epidermal Growth Factor Receptor Transactivation by Angiotensin II Requires Reactive Oxygen Species in Vascular Smooth Muscle Cells Arterioscler Thromb Vasc Biol, April 1, 2001; 21(4): 489 - 495. [Abstract] [Full Text] [PDF]

				M. M. Martin, B. M. Willardson, G. F. Burton, C. R. White, J. N. McLaughlin, S. M. Bray, J. W. Ogilvie Jr., and T. S. Elton Human Angiotensin II Type 1 Receptor Isoforms Encoded by Messenger RNA Splice Variants Are Functionally Distinct Mol. Endocrinol., February 1, 2001; 15(2): 281 - 293. [Abstract] [Full Text]

				H. Iwasaki, M. Shichiri, F. Marumo, and Y. Hirata Adrenomedullin Stimulates Proline-Rich Tyrosine Kinase 2 in Vascular Smooth Muscle Cells Endocrinology, February 1, 2001; 142(2): 564 - 572. [Abstract] [Full Text] [PDF]

				U. Kintscher, S. Wakino, S. Kim, E. Fleck, W. A. Hsueh, and R. E. Law Angiotensin II Induces Migration and Pyk2/Paxillin Phosphorylation of Human Monocytes Hypertension, February 1, 2001; 37(2): 587 - 593. [Abstract] [Full Text] [PDF]

				E. Feraille and A. Doucet Sodium-Potassium-Adenosinetriphosphatase-Dependent Sodium Transport in the Kidney: Hormonal Control Physiol Rev, January 1, 2001; 81(1): 345 - 418. [Abstract] [Full Text] [PDF]

				P. Rocic, G. Govindarajan, A. Sabri, and P. A. Lucchesi A role for PYK2 in regulation of ERK1/2 MAP kinases and PI 3-kinase by ANG II in vascular smooth muscle Am J Physiol Cell Physiol, January 1, 2001; 280(1): C90 - C99. [Abstract] [Full Text] [PDF]

				B. Schieffer, M. Luchtefeld, S. Braun, A. Hilfiker, D. Hilfiker-Kleiner, and H. Drexler Role of NAD(P)H Oxidase in Angiotensin II-Induced JAK/STAT Signaling and Cytokine Induction Circ. Res., December 8, 2000; 87(12): 1195 - 1201. [Abstract] [Full Text] [PDF]

				R. M. Touyz and E. L. Schiffrin Signal Transduction Mechanisms Mediating the Physiological and Pathophysiological Actions of Angiotensin II in Vascular Smooth Muscle Cells Pharmacol. Rev., December 1, 2000; 52(4): 639 - 672. [Abstract] [Full Text] [PDF]

				G. D. Frank, S. Eguchi, T. Yamakawa, S.-i. Tanaka, T. Inagami, and E. D. Motley Involvement of Reactive Oxygen Species in the Activation of Tyrosine Kinase and Extracellular Signal-Regulated Kinase by Angiotensin II Endocrinology, September 1, 2000; 141(9): 3120 - 3126. [Abstract] [Full Text] [PDF]

				A. D Hughes AT 1-signalling in vascular smooth muscle Journal of Renin-Angiotensin-Aldosterone System, June 1, 2000; 1(2): 125 - 130. [PDF]

				H. Tang, T. Nishishita, T. Fitzgerald, E. J. Landon, and T. Inagami Inhibition of AT1 Receptor Internalization by Concanavalin A Blocks Angiotensin II-induced ERK Activation in Vascular Smooth Muscle Cells. INVOLVEMENT OF EPIDERMAL GROWTH FACTOR RECEPTOR PROTEOLYSIS BUT NOT AT1 RECEPTOR INTERNALIZATION J. Biol. Chem., April 28, 2000; 275(18): 13420 - 13426. [Abstract] [Full Text] [PDF]

				S. J. Keely, S. O. Calandrella, and K. E. Barrett Carbachol-stimulated Transactivation of Epidermal Growth Factor Receptor and Mitogen-activated Protein Kinase in T84 Cells Is Mediated by Intracellular Ca2+, PYK-2, and p60src J. Biol. Chem., April 21, 2000; 275(17): 12619 - 12625. [Abstract] [Full Text] [PDF]

				K.A. DeFea, J. Zalevsky, M.S. Thoma, O. Dery, R.D. Mullins, and N.W. Bunnett {beta}-Arrestin-Dependent Endocytosis of Proteinase-Activated Receptor 2 Is Required for Intracellular Targeting of Activated Erk1/2 J. Cell Biol., March 20, 2000; 148(6): 1267 - 1282. [Abstract] [Full Text] [PDF]

				H. Tang, Z. J. Zhao, E. J. Landon, and T. Inagami Regulation of Calcium-sensitive Tyrosine Kinase Pyk2 by Angiotensin II in Endothelial Cells. ROLES OF Yes TYROSINE KINASE AND TYROSINE PHOSPHATASE SHP-2 J. Biol. Chem., March 17, 2000; 275(12): 8389 - 8396. [Abstract] [Full Text] [PDF]

				J. Egea, C. Espinet, R. M. Soler, S. Peiró, N. Rocamora, and J. X. Comella Nerve Growth Factor Activation of the Extracellular Signal-Regulated Kinase Pathway Is Modulated by Ca2+ and Calmodulin Mol. Cell. Biol., March 15, 2000; 20(6): 1931 - 1946. [Abstract] [Full Text]

				G. Venkatakrishnan, R. Salgia, and J. E. Groopman Chemokine Receptors CXCR-1/2 Activate Mitogen-activated Protein Kinase via the Epidermal Growth Factor Receptor in Ovarian Cancer Cells J. Biol. Chem., March 15, 2000; 275(10): 6868 - 6875. [Abstract] [Full Text] [PDF]

				B. Seo, E. W. Choy, S. Maudsley, W. E. Miller, B. A. Wilson, and L. M. Luttrell Pasteurella multocida Toxin Stimulates Mitogen-activated Protein Kinase via Gq/11-dependent Transactivation of the Epidermal Growth Factor Receptor J. Biol. Chem., January 21, 2000; 275(3): 2239 - 2245. [Abstract] [Full Text] [PDF]

				S. Eguchi, H. Iwasaki, H. Ueno, G. D. Frank, E. D. Motley, K. Eguchi, F. Marumo, Y. Hirata, and T. Inagami Intracellular Signaling of Angiotensin II-induced p70 S6 Kinase Phosphorylation at Ser411 in Vascular Smooth Muscle Cells. POSSIBLE REQUIREMENT OF EPIDERMAL GROWTH FACTOR RECEPTOR, RAS, EXTRACELLULAR SIGNAL-REGULATED KINASE, AND AKT J. Biol. Chem., December 24, 1999; 274(52): 36843 - 36851. [Abstract] [Full Text] [PDF]

				J. A. Cole Parathyroid Hormone Activates Mitogen-Activated Protein Kinase in Opossum Kidney Cells Endocrinology, December 1, 1999; 140(12): 5771 - 5779. [Abstract] [Full Text]

				G. Carpenter Employment of the Epidermal Growth Factor Receptor in Growth Factor-Independent Signaling Pathways J. Cell Biol., August 23, 1999; 146(4): 697 - 702. [Full Text] [PDF]

				S. Eguchi, P. J. Dempsey, G. D. Frank, E. D. Motley, and T. Inagami Activation of MAPKs by Angiotensin II in Vascular Smooth Muscle Cells. METALLOPROTEASE-DEPENDENT EGF RECEPTOR ACTIVATION IS REQUIRED FOR ACTIVATION OF ERK AND p38 MAPK BUT NOT FOR JNK J. Biol. Chem., March 9, 2001; 276(11): 7957 - 7962. [Abstract] [Full Text] [PDF]

				A. Sorokin, P. Kozlowski, L. Graves, and A. Philip Protein-tyrosine Kinase Pyk2 Mediates Endothelin-induced p38 MAPK Activation in Glomerular Mesangial Cells J. Biol. Chem., June 8, 2001; 276(24): 21521 - 21528. [Abstract] [Full Text] [PDF]

				P. Rocic and P. A. Lucchesi Down-regulation by Antisense Oligonucleotides Establishes a Role for the Proline-rich Tyrosine Kinase PYK2 in Angiotensin II-induced Signaling in Vascular Smooth Muscle J. Biol. Chem., June 8, 2001; 276(24): 21902 - 21906. [Abstract] [Full Text] [PDF]

				J. S. Grewal, L. M. Luttrell, and J. R. Raymond G Protein-coupled Receptors Desensitize and Down-regulate Epidermal Growth Factor Receptors in Renal Mesangial Cells J. Biol. Chem., July 13, 2001; 276(29): 27335 - 27344. [Abstract] [Full Text] [PDF]

				S. Heeneman, J. Haendeler, Y. Saito, M. Ishida, and B. C. Berk Angiotensin II Induces Transactivation of Two Different Populations of the Platelet-derived Growth Factor beta Receptor. KEY ROLE FOR THE p66 ADAPTOR PROTEIN Shc J. Biol. Chem., May 19, 2000; 275(21): 15926 - 15932. [Abstract] [Full Text] [PDF]

				K. A. DeFea, Z. D. Vaughn, E. M. O'Bryan, D. Nishijima, O. Dery, and N. W. Bunnett The proliferative and antiapoptotic effects of substance P are facilitated by formation of a beta -arrestin-dependent scaffolding complex PNAS, September 26, 2000; 97(20): 11086 - 11091. [Abstract] [Full Text] [PDF]

				S. S. Wu, T. Chiu, and E. Rozengurt ANG II and LPA induce Pyk2 tyrosine phosphorylation in intestinal epithelial cells: role of Ca2+, PKC, and Rho kinase Am J Physiol Cell Physiol, June 1, 2002; 282(6): C1432 - C1444. [Abstract] [Full Text] [PDF]

				R. Ginnan and H. A. Singer CaM kinase II-dependent activation of tyrosine kinases and ERK1/2 in vascular smooth muscle Am J Physiol Cell Physiol, April 1, 2002; 282(4): C754 - C761. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Eguchi, S. Articles by Hirata, Y. Search for Related Content PubMed PubMed Citation Articles by Eguchi, S. Articles by Hirata, Y.