Published online before print October 21, 2004, doi: 10.1161/01.ATV.0000148449.92035.3a
© 2004 American Heart Association, Inc.
Vascular Biology |
Angiotensin II–Induced Protein Kinase D Activation Is Regulated by Protein Kinase C
and Mediated via the Angiotensin II Type 1 Receptor in Vascular Smooth Muscle Cells
From the Department of Pathobiology (M.T., X.X., M.-Z.C.), the University of Tennessee, Knoxville; and the Institute of Molecular Oncology (M.O.), Showa University, Shinagawa-ku, Tokyo, Japan.
Correspondence to Mei-Zhen Cui, PhD, Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, 2407 River Dr, Knoxville, TN 37996. E-mail cuim{at}utk.edu
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Abstract |
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Objective— Angiotensin II (Ang II), through its specific signaling cascades, exerts multiple effects on vascular smooth muscle cells (SMCs). It has been shown that Ang II stimulates activation of protein kinase D (PKD), a member of a new class of serine–threonine kinases. However, little is known regarding the upstream cascade of the intracellular signaling that leads to PKD activation. In the present study, we investigated upstream molecules that mediate Ang II–induced PKD activation in SMCs.
Methods and Results— Protein kinase C (PKC) inhibitors completely block Ang II–induced PKD activation, and pretreatment with phorbol 12,13-dibutyrate downregulates Ang II–induced PKD activation, indicating that classical or novel isoforms of PKC mediate Ang II–induced PKD activation. Furthermore, the finding that rottlerin, a PKC
-specific inhibitor, blocks PKD activation suggests that PKC, a member of novel PKCs, mediates Ang II–induced PKD activation. By using dominant-negative approaches, our results demonstrate that expression of the dominant-negative PKC, but neither the dominant-negative form of PKC
nor PKC
, inhibits PKD activation. These results further substantiate the finding that Ang II–induced PKD activation is mediated by PKC. Moreover, using selective Ang II receptor antagonists, our data show that the Ang II type 1 (AT1) receptor but not the AT2 mediates Ang II–stimulated PKD activation.
Conclusions— This study reveals for the first time that Ang II–induced PKD activation is mediated via AT1 and regulated by PKC in living cells. These data may provide new insights into molecular mechanisms involved in Ang II–induced physiological and pathological events.
The results of our study reveal for the first time that Ang II–induced PKD activation is mediated via AT1 and regulated by PKC in living cells. These data may provide new insights into molecular mechanisms involved in Ang II–induced physiological and pathological events.
Key Words: protein kinase D • PKC • angiotensin II • angiotensin II receptors • signal transduction
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Angiotensin II (Ang II) is a multifunctional hormone that has various effects on vascular smooth muscle cells (SMCs). These effects include promoting cell growth, modulating cell contraction, and influencing cell migration. Ang II–mediated signaling pathways in SMCs are highly complex. It has been reported previously that Ang II stimulates protein kinase D (PKD) activation in rabbit SMCs;1 however, the regulatory mechanism, specifically the signaling cascades that mediate Ang II–induced PKD activation, has not been defined.
PKD, also known as protein kinase Cµ (PKCµ), is a serine–threonine protein kinase with structural, enzymological, and regulatory properties different from those of PKC family members.2 The most distinct characteristics of PKD are the presence of a catalytic domain distantly related to Ca2+-regulated kinases, a pleckstrin homology region that regulates enzyme activity, and a highly hydrophobic stretch of amino acids in its N-terminal region. PKD has been implicated in the regulation of a variety of cellular events including Na+/H+ antiport activity, Golgi organization and function, protein transport, nuclear factor 
B (NF-B)–mediated gene expression, and cellular invasion.2
PKD can be activated within intact cells by pharmacological agents such as biologically active phorbol esters and growth factors, as well as by antigen–receptor engagement via PKC-dependent and PKC-independent pathways.3–5 Studies have shown that overexpression of the constitutively active forms of novel PKC, PKC
, and PKC
can fully activate PKD, whereas overexpression of atypical PKC does not activate PKD.6,7 Furthermore, PKC and PKC have been reported to interact with PKD.8 Interestingly, we found recently that PKC, a member of novel PKCs, mediates thrombin-induced PKD activation.9 PKC-independent activation of PKD has been reported to occur as the result of direct interaction of PKD with ß
subunits of G-protein and the caspase-mediated cleavage of PKD.4,5 However, the upstream signaling molecules, including the particular receptors and specific PKC isoforms, which mediate PKD activation in response to specific cellular stimuli in the PKD activation pathways, remain elusive.
Here we show that: (1) PKC inhibitors GF 109203X and Ro 318220 block Ang II–stimulated PKD activation; (2) rottlerin, a pharmacological inhibitor of PKC, inhibits activation of PKD; (3) overexpression of a dominant-negative PKC by using an adenovirus system diminishes Ang II–induced PKD activation in SMCs, whereas expression of dominant-negative forms of PKC and PKC do not affect Ang II–induced PKD activation; and (4) the Ang II type 1 (AT1) receptor antagonist Losartan, but not PD123319, an antagonist of AT2, completely blocks Ang II–induced PKD activation. Thus, our results reveal that PKC and AT1 mediate Ang II–induced PKD activation in vascular SMCs.
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Materials and Methods |
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Materials
Reagents were obtained as follows: Ang II from Sigma; protein kinase inhibitors Ro 318220, GF 109203X, and rottlerin from Biomol; antibodies against PKC
and PKC from BD Transduction Laboratories; antibody against PKC from Upstate Biotechnology; antibodies against PKD, phospho-PKC (S729), and phospho-PKC (Y311) from Santa Cruz Biotechnology; antibodies against phospho-PKC (T505), phospho-PKC isoforms 
, ß, and , and phospho-PKD (pS744/748 and pS916) from Cell Signaling Technology; Losartan from Merck Pharmaceutical; Saralasin and PD123319 from Sigma-Aldrich; and [-32P]ATP from ICN Biomedicals.
Cell Culture
Rat aortic SMCs were isolated from explants of excised aortas of rats and maintained in DMEM containing 10% FBS. SMCs between passages 6 and 17 were used in this study.
Adenovirus Constructs and Adenoviral Infection of SMCs
Adenoviruses encoding mouse PKC isotypes ( or ) were constructed as described previously.10 Adenoviral wild-type and dominant-negative PKC constructs were kindly provided by Dr Wataru Ogawa (Kobe University, Japan). SMCs in DMEM containing 10% FBS were infected for 24 hours with either wild-type or dominant-negative PKC isotypes.
Western Blotting Analysis
SMCs or SMCs infected with virus expression vectors were serum-starved in serum-free medium for 24 hours before treatment with Ang II. After treatment with Ang II, cells were lysed and subjected to Western blot analysis as described previously.11
Detection of PKD Activation
PKD phosphorylation was detected by using phosphospecific antibodies. Cell lysates were immunoblotted using phosphospecific antibodies to Ser744/748 and Ser916. The residues Ser744 and Ser748 in the activation loop of PKD have been shown to be phosphorylated during PKD activation.12 Ser916, an autophosphorylation site, is phosphorylated when PKD is activated.13 Exogenous substrate phosphorylation by immunoprecipitated PKD was determined as described previously.3
Detection of PKC Activation
Cell lysates were immunoblotted using phosphospecific antibodies. The following phosphospecific antibodies were used: phospho-PKC (Y311) and phospho-PKC (T505) antibodies to detect PKC activation, phospho-PKC/ßII (T638/641) antibody to detect PKC/ßII activation, phospho-PKC/
(T410/403) antibody to detect PKC/ activation, and phospho-PKC (S729) antibody to detect PKC activation.
Statistical Analysis
The means±SEs were calculated using Excel Statistical Software and statistical significance (P value) was determined by 2-tailed Student t test. A value of P<0.05 was considered statistically significant.
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Results |
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Ang II Induces PKD Activation in Rat Aortic SMCs in a Time- and Dose-Dependent Manner
PKD activation involves the phosphorylation of Ser744 and Ser748 within the activation loop of the catalytic domain of PKD.12 PKD can also be autophosphorylated at the Ser916 site during activation.13 Ang II–induced PKD activation was determined by using 2 commercially available phospho-PKD–specific antibodies, 1 of which recognizes the phosphorylated Ser744 and phosphorylated Ser748 and the other that recognizes phosphorylated Ser916. By using these antibodies, we observed that Ang II rapidly induced PKD phosphorylation within 45 seconds, and the activation reached a maximum between 2 and 16 minutes and was sustained for hours (Figure 1A). We also observed that Ang II induces PKD activation in a concentration-dependent manner. Ang II induced PKD activation at a concentration as low as 0.25 nmol/L and achieved maximal activation at 100 nmol/L (Figure I, available online at http://atvb.ahajournals.org). We further confirmed PKD activation by using an exogenous substrate. The synthetic peptide syntide-2 has been identified as an efficient substrate for the catalytic domain of PKD and for the full-length PKD.3 As shown in Figure 1B, PKD activity immunoprecipitated from lysates of SMC was rapidly induced by Ang II.
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AT1 but not AT2 Mediates Ang II–Induced PKD Activation
Ang II is known to exert its biological effects through binding to 2 receptor subtypes: AT1 and AT2, which belong to the G-protein–coupled receptor super family.14 To determine which subtype of Ang II receptors mediates Ang II–induced PKD activation in SMCs, we examined the effect of specific antagonists on induction of PKD. SMCs were pretreated for 40 minutes with either Saralasin, an antagonist of AT1 and AT2, or PD123319, an antagonist specific to AT2, and then stimulated with Ang II for 3 minutes. As shown in Figure 2A, Saralasin at the low dose of 5 µmol/L completely blocked PKD phosphorylation induced by Ang II, whereas the AT2-specific antagonist PD123319 had no effect on Ang II activation of PKD in SMC. These results suggest that AT1 mediates Ang II–induced PKD activation. To further determine the specific involvement of AT1, we pretreated SMCs with the AT1-specific antagonist Losartan. As demonstrated in Figure 2B, Losartan inhibited Ang II–induced PKD activation in a dose-dependent manner. These data reveal that Ang II–induced PKD activation is specifically mediated by AT1 but not AT2 in living cells.
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Ang II Stimulates PKD Activation Through a PKC-Dependent Pathway
To determine whether PKC activation is involved in Ang II–induced PKD activation in SMCs, we examined the effect of PKC inhibitors on PKD activation stimulated by Ang II. Quiescent SMCs were treated with PKC inhibitors GF 109203X or Ro 318220 for 40 minutes before exposure to Ang II (0.1 µmol/L) for 3 minutes. As shown in Figure 3A, GF 109203X at a concentration as low as 0.5 µmol/L completely blocked PKD activation. Ang II–induced PKD phosphorylation was also blocked by Ro 318220 in a concentration-dependent fashion (Figure II, available online at http://atvb.ahajournals.org). These data suggest that PKC is involved in the Ang II–stimulated PKD activation in SMC.
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We also examined whether the mitogen-activated protein kinase/kinase (MEK) inhibitor Uo126, phosphoinositide 3-kinase (PI3K) inhibitor LY 294002, and p38 mitogen-activated protein kinase (MAPK) inhibitor SB-203580 affect PKD activation. As shown in Figure III (available online at http://atvb.ahajournals.org), these inhibitors completely blocked activation of extracellular signal–regulated kinase (ERK)1/2, PI3K, and p38MAPK. However, under the same experimental conditions, none of these inhibitors had any effect on Ang II–induced PKD activation (Figure 3B). These results indicate that PKC activation, but not the activation of ERK1/2, PI3K, or p38 MAPK is required for Ang II–induced PKD activation in SMC.
Phorbol 12,13-Dibutyrate Treatment Desensitizes Ang II Activation of PKD
It has been reported that phorbol ester–responsive PKC isoforms (ie, classical and novel PKC isoforms) are downregulated by prolonged treatment with phorbol 12,13-dibutyrate (PDBu; 1 µmol/L for 24 hour) because of the degradation of these PKC isoforms in SMCs.15 To determine the role of specific PKC isoforms in the activation of PKD by Ang II, we first examined whether prolonged treatment of PDBu affects Ang II–induced PKD activation. We found that prolonged treatment of PDBu completely blocked Ang II–induced PKD activation (Figure IV, available online at http://atvb.ahajournals.org). Given the fact that prolonged treatment with PDBu does not cause the PKD degradation,16 these results suggest that the classical or novel PKC isoforms are involved in Ang II–mediated PKD activation.
PKC Is Rapidly Activated by Ang II in Aortic SMCs
Next, we attempted to determine which specific isotype of PKC is required for PKD activation. Previous studies of SMCs have shown that several members of PKC isoforms including PKC, ß, , , and are expressed in SMCs,15,17–20 and among them, PKC is the most abundant in rat aortic SMCs.21 We first determined which PKC isoforms in SMCs are activated by Ang II. As shown in Figure 4A, marked phosphorylation of PKC at Y311 and T505 was rapidly induced within 45 seconds during Ang II treatment of SMCs; in contrast, Ang II did not induce detectable phosphorylation of the PKC/ß, PKC, or PKC (Figure 4A). The Ang II–induced PKC activation was completely inhibited by PKC inhibitors Ro 318220 and GF 109203X (Figure VA and VB, available online at http://atvb.ahajournals.org).
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PKC Inhibitor Rottlerin Blocks PKD Activation
The rapid and prominent activation of PKC by Ang II prompted us to examine whether the activation of PKC contributed to Ang II–induced PKD activation by determining the effect of the PKC inhibitor rottlerin. Rottlerin has been reported to selectively inhibit PKC activation (IC50=3 to 6 µmol/L) and is 5- to 10-fold more potent than the and ß isoforms, and 13- to 33-fold more potent than the , , and isoforms.22 SMCs were pretreated with various concentrations of rottlerin for 40 minutes, followed by stimulation with Ang II for 3 minutes. As shown in Figure 4B, pretreatment with the PKC inhibitor rottlerin abrogated Ang II–triggered PKD activation in a concentration-dependent fashion. This result strongly suggests that Ang II–induced PKD activation is dependent on PKC activity in SMCs.
Dominant-Negative PKC Blocks Ang II–Induced PKD Activation
To further substantiate the role of PKC in mediating Ang II–induced PKD activation in living cells, we examined the effect of the dominant-negative form of PKC on Ang II–induced PKD activation. The dominant-negative nature of the ATP-binding site mutant PKC has been characterized previously.23 We used recombinant adenovirus constructs to overexpress specific PKC isoforms in SMCs and determined the effects of these dominant-negative isoforms of PKC on Ang II–induced cellular PKD activation. As shown in Figure 5, infection of rat aortic SMCs with recombinant adenovirus constructs expressing the wild-type or dominant-negative PKCs resulted in robust expression of these PKC isoforms (Figure 5A through 5C, third panel). As shown in Figure 5A, at a multiplicity of infection (moi) of 30, infection of SMCs with an adenovirus construct that encodes for the dominant-negative PKC blocked Ang II–induced PKD activation (by 92%), as determined by measuring PKD phosphorylation at Ser744/Ser748. At an moi of 60, dominant-negative PKC almost completely (98%) blocked PKD phosphorylation at Ser744/Ser748. In contrast, neither dominant-negative PKC and PKC, nor wild-type PKC and PKC, at the same moi, affected PKD activation (Figure 5B and 5C). It was also noted that overexpression of the wild-type PKC had no detectable effect on Ang II–induced PKD activity, suggesting that the endogenous PKC is sufficient for mediating Ang II induction of PKD activation in SMCs. To further determine the specificity of the effect of dominant-negative PKC on Ang II activation of PKD, we examined whether dominant PKC affected Ang II–induced c-Jun amino-terminal kinase (JNK) activation. As shown in the fifth panel of Figure 5A, the dominant-negative PKC had no effect on Ang II–induced activation of JNK in the same SMCs, indicating that PKC selectively mediates Ang II–induced PKD activation rather than functioning as a general modulator of Ang II–induced cellular signaling. Together, these results indicate that PKC plays a specific role in mediating Ang II–induced PKD activation in SMCs.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our results presented above reveal, for the first time, that Ang II–induced PKD activation is mediated by PKC
and the AT1 receptor in intact cells. We used multiple approaches to determine and confirm the specific role of PKC in mediating Ang II–induced PKD activation. The general PKC inhibitors GF109203X and Ro 318220 blocked Ang II–induced PKD activation in a concentration-dependent manner, suggesting that Ang II induces PKD activation through a PKC-dependent pathway in SMCs. Our data also show that the potent PI3K inhibitor LY-294002 (50 µmol/L), the MEK inhibitor U-0126 (10 µmol/L), and the p38 MAPK inhibitor SB-203580 (10 µmol/L) have no effect on the PKD activation induced by Ang II, indicating that neither PI3K nor MAPK is involved in a major pathway that mediates Ang II–induced PKD activation. The prolonged treatment with PDBu abolished Ang II activation of PKD, further suggesting the role of classical or novel PKC isoforms in mediating PKD activation by Ang II. The findings that Ang II induces activation of PKC in SMCs (Figure 4A) and that the PKC inhibitor rottlerin blocked Ang II–induced PKD activation in a concentration-dependent manner (Figure 4B) strongly suggest the functional involvement of PKC in Ang II–induced PKD activation. To further substantiate the specific role of PKC, we used the dominant-negative approach by using an adenovirus expression system to express the wild-type and dominant-negative forms of PKC, , and in SMCs. Our results reveal that overexpression of the dominant-negative PKC but not the dominant-negative PKC and PKC strongly inhibits Ang II–induced PKD activation (Figure 5). Together, these data indicate that Ang II activates PKD in living cells via activation of PKC, a member of the novel PKCs.
On the basis of the observations that PKD activity was enhanced during transient coexpression with constitutively active PKC, PKC,6,24,25 and PKC,7 recent studies have suggested that PKC, PKC, and PKC may function as potential upstream kinases and account for the PKC-dependent activation of PKD. However, the functional relationship between endogenous novel PKCs (PKC, PKC, and PKC) and PKD in living cells, in response to physiological or pathological stimuli, remains elusive. In a previous study, we provided the first evidence that PKC regulates an extracellular stimulus: thrombin-induced PKD activation in SMCs.9 In the present study, our data demonstrate that the multifunctional hormone Ang II–induced PKD activation is also mediated by PKC in SMCs. These findings lead to an important notion that in intact cells, PKC is the major, if not the only, mediator of PKD activation in response to various physiological and biological stimuli. This notion is also supported by a very recent study showing that PKC selectively mediates PKD activation in oxidative stress-induced signaling in human cell line (HeLa) cells.26
The data presented in this study indicate that Ang II via AT1 receptor but not AT2 receptor triggers activation of PKC, and PKC in turn activates PKD by phosphorylation of its loop residues S744 and S748. This result is supported by our recent observation that PKC physically interacts with PKD in rat aortic SMCs.9 The fact that pertussis toxin does not block Ang II–induced PKD activation (M.T., unpublished observation, 2004) suggests other types of G-protein, other than Gi/o, are involved in Ang II–regulated PKD activation. Studies have shown that stimulation of COS-7 cells with H2O2 activates PKC,27 and that Ang II–stimulated production of reactive oxygen species (ROS) was detected in SMCs.28 However, to date, whether Ang II–induced activation of PKC is mediated by ROS or whether PKC activation in fact leads to generation of ROS in SMCs remains unclear.
In vascular SMCs, Ang II has been shown to induce expression of several proinflammatory genes through activation of NF-B.29 These genes include monocyte chemoattractant protein-1, vascular cell adhesion molecule-1, interleukin-6, and tissue factor. It has been reported that PKC and PKD mediate oxidative stress–induced NF-B activation in HeLa cells.26 Therefore, it is possible that PKC and PKD may play a role in mediating Ang II–induced NF-B activation that leads to various gene expression in vascular SMCs.
In summary, our results reveal that the Ang II–triggered signaling pathway that leads to PKD activation is specifically mediated by AT1 and PKC in vascular SMCs. These findings may provide new insights into molecular mechanisms involved in Ang II–mediated physiological or pathological events in vascular SMCs.
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Acknowledgments |
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This work was supported by a grant-in-aid from the American Heart Association (to M.-Z. C.) and grant NS42314 from the National Institutes of Health (to X.M.X.). We thank Dr M. Donald McGavin for critical reading of the manuscript.
Received June 28, 2004; accepted October 12, 2004.
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References |
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1. Abedi H, Rozengurt E, Zachary I. Rapid activation of the novel serine/threonine protein kinase, protein kinase D by phorbol esters, angiotensin II and PDGF-BB in vascular smooth muscle cells. FEBS Lett. 1998; 427: 209–212.[CrossRef][Medline] [Order article via Infotrieve]
2. Lint JV, Rykx A, Vantus T, Vandenheede JR. Getting to know protein kinase D. Int J Biochem Cell Biol. 2002; 34: 577–581.[CrossRef][Medline] [Order article via Infotrieve]
3. Zugaza JL, Waldron RT, Sinnett-Smith J, Rozengurt E. Bombesin, vasopressin, endothelin, bradykinin, and platelet-derived growth factor rapidly activate protein kinase D through a protein kinase C-dependent signal transduction pathway. J Biol Chem. 1997; 272: 23952–23960.
4. Jamora C, Yamanouye N, Van Lint J, Laudenslager J, Vandenheede JR, Faulkner DJ, Malhotra V. Gß-mediated regulation of Golgi organization is through the direct activation of protein kinase D. Cell. 1999; 98: 59–68.[CrossRef][Medline]
[Order article via Infotrieve]
5. Endo K, Oki E, Biedermann V, Kojima H, Yoshida K, Johannes FJ, Kufe D, Datta R. Proteolytic cleavage and activation of protein kinase C [micro] by caspase-3 in the apoptotic response of cells to 1-ß-D-arabinofuranosylcytosine and other genotoxic agents. J Biol Chem. 2000; 275: 18476–18481.
6. Zugaza JL, Sinnett-Smith J, Van Lint J, Rozengurt E. Protein kinase D (PKD) activation in intact cells through a protein kinase C-dependent signal transduction pathway. EMBO J. 1996; 15: 6220–6230.[Medline] [Order article via Infotrieve]
7. Yuan J, Bae D, Cantrell D, Nel AE, Rozengurt E. Protein kinase D is a downstream target of protein kinase Ctheta. Biochem Biophys Res Commun. 2002; 291: 444–452.[CrossRef][Medline] [Order article via Infotrieve]
8. Waldron RT, Iglesias T, Rozengurt E. The pleckstrin homology domain of protein kinase D interacts preferentially with the eta isoform of protein kinase C. J Biol Chem. 1999; 274: 9224–9230.
9. Tan M, Xu X, Ohba M, Ogawa W, Cui MZ. Thrombin rapidly induces protein kinase D phosphorylation, and protein kinase C mediates the activation. J Biol Chem. 2003; 278: 2824–2828.
10. Ohba M, Ishino K, Kashiwagi M, Kawabe S, Chida K, Huh NH, Kuroki T. Induction of differentiation in normal human keratinocytes by adenovirus-mediated introduction of the eta and delta isoforms of protein kinase C. Mol Cell Biol,. 1998; 18: 5199–5207.
11. Xu X, Shi YC, Gao W, Mao G, Zhao G, Agrawal S, Chisolm GM, Sui D, Cui MZ. The novel presenilin-1-associated protein is a proapoptotic mitochondrial protein. J Biol Chem. 2002; 277: 48913–48922.
12. Iglesias T, Waldron RT, Rozengurt E. Identification of in vivo phosphorylation sites required for protein kinase D activation. J Biol Chem. 1998; 273: 27662–27667.
13. Matthews SA, Rozengurt E, Cantrell D. Characterization of serine 916 as an in vivo autophosphorylation site for protein kinase D/Protein kinase Cmu. J Biol Chem. 1999; 274: 26543–26549.
14. Touyz RM, Berry C. Recent advances in angiotensin II signaling. Braz J Med Biol Res. 2002; 35: 1001–1015.[Medline] [Order article via Infotrieve]
15. Liao DF, Monia B, Dean N, Berk BC. Protein kinase C-zeta mediates angiotensin II activation of ERK1/2 in vascular smooth muscle cells. J Biol Chem. 1997; 272: 6146–6150.
16. Chiu T, Rozengurt E. PKD in intestinal epithelial cells: rapid activation by phorbol esters, LPA, and angiotensin through PKC. Am J Physiol Cell Physiol. 2001; 280: C929–C942.
17. Assender JW, Kontny E, Fredholm BB. Expression of protein kinase C isoforms in smooth muscle cells in various states of differentiation. FEBS Lett. 1994; 342: 76–80.[CrossRef][Medline] [Order article via Infotrieve]
18. Dixon BS, Sharma RV, Dickerson T, Fortune J. Bradykinin and angiotensin II: activation of protein kinase C in arterial smooth muscle. Am J Physiol. 1994; 266: C1406–C1420.
19. Morgan KG, Leinweber BD. PKC-dependent signaling mechanisms in differentiated smooth muscle. Acta Physiol Scand. 1998; 164: 495–505.[CrossRef][Medline] [Order article via Infotrieve]
20. Pang L, Nie M, Corbett L, Donnelly R, Gray S, Knox AJ. Protein kinase C- mediates bradykinin-induced cyclooxygenase-2 expression in human airway smooth muscle cells. FASEB J. 2002; 16: 1435–1437.
21. Fukumoto S, Nishizawa Y, Hosoi M Koyama H, Yamakawa K, Ohno S, Morii H. Protein kinase C inhibits the proliferation of vascular smooth muscle cells by suppressing G1 cyclin expression. J Biol Chem. 1997; 272: 13816–13822.
22. Gschwendt M, Muller HJ, Kielbassa K, Zang R, Kittstein W, Rincke G, Marks F. Rottlerin, a novel protein kinase inhibitor. Biochem Biophys Res Commun. 1994; 199: 93–98.[CrossRef][Medline] [Order article via Infotrieve]
23. Li W, Michieli P, Alimandi M, Lorenzi MV, Wu Y, Wang LH, Heidaran MA, Pierce JH. Expression of an ATP binding mutant of PKC- inhibits Sis-induced transformation of NIH3T3 cells. Oncogene. 1996; 13: 731–737.[Medline]
[Order article via Infotrieve]
24. Brandlin I, Hubner S, Eiseler T, Martinez-Moya M, Horschinek A Hausser A, Link G, Rupp S, Storz P, Pfizenmaier K, Johannes FJ. Protein kinase C (PKC)eta-mediated PKC mu activation modulates ERK and JNK signal pathways. J Biol Chem. 2002; 277: 6490–6496.
25. Brandlin I, Eiseler T, Salowsky R, Johannes FJ. Protein kinase C(mu) regulation of the JNK pathway is triggered via phosphoinositide-dependent kinase 1 and protein kinase C(). J Biol Chem. 2002; 277: 45451–45457.
26. Storz P, Doppler H, Toker A. Protein kinase C selectively regulates protein kinase D-dependent activation of NF-kappaB in oxidative stress signaling. Mol Cell Biol. 2004; 24: 2614–2626.
27. Konishi H, Tanaka M, Takemura Y, Matsuzaki H, Ono Y, UKikkawa, Nishizuka Y. Activation of protein kinase C by tyrosine phosphorylation in response to H2O2. Proc Natl Acad Sci U S A. 1997; 94: 11233–11237.
28. Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res. 1994; 74: 1141–1148.
29. Phillips MI, Kagiyama S. Angiotensin II as a pro-inflammatory mediator. Curr Opin Investig Drugs. 2002; 3: 569–577.[Medline] [Order article via Infotrieve]
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