Electroporation of pp60c− Antibodies Inhibits the Angiotensin II Activation of Phospholipase C-γ1 in Rat Aortic Smooth Muscle Cells

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

doi:10.1074/jbc.270.26.15734

Cited by 169 publications

(109 citation statements)

References 23 publications

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“…The effects of Gq-protein-mediated activation of the AT1 receptor varies in different tissues, including vasoconstriction, aldosterone release, renal sodium reabsorption, adrenergic facilitation, VSMC hypertrophy and cardiac myocyte hyperplasia. In VSMC, Ang II activates numerous tyrosine phosphorylated proteins, which share similarity with that the response to growth factors and cytokines, including the JAK kinase family, JAK2 and Tyk2 [38], [39], the Src kinase family, Fyn and c-Src [40], [41], the growth factor receptor family, platelet-derived growth factor receptor (PDGFR), epidermal growth factor receptor (EGFR) and insulin growth factor receptor (IGFR) [42][43][44][45][46], the STAT transcriptional factor family [47], [48], and the cell adhesion proteins, Paxillin and focal adhesion kinase (FAK) [49], [50]. In addition, the adaptor protein SHC, tyrosine phosphatase SHP2, PLC-γ1, p130CAS and insulin receptor substance 1 (IRS1) are also tyrosinephosphorylated in response to Ang II [42], [51][52][53].…”

Section: Signaling Transduction Pathways Of the At1 Receptormentioning

confidence: 99%

The angiotensin II type 1 receptor and receptor-associated proteins

et al. 2001

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The mechanisms of regulation, activation and signal transduction of the angiotensin II (Ang II) type 1 (AT1) receptor have been studied extensively in the decade after its cloning. The AT1 receptor is a major component of the renin-angiotensin system (RAS). It mediates the classical biological actions of Ang II. Among the structures required for regulation and activation of the receptor, its carboxyl-terminal region plays crucial roles in receptor internalization, desensitization and phosphorylation. The mechanisms involved in heterotrimeric G-protein coupling to the receptor, activation of the downstream signaling pathway by G proteins and the Ang II signal transduction pathways leading to specific cellular responses are discussed. In addition, recent work on the identification and characterization of novel proteins associated with carboxyl-terminus of the AT1 receptor is presented. These novel proteins will advance our understanding of how the receptor is internalized and recycled as they provide molecular mechanisms for the activation and regulation of G-protein-coupled receptors.

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Section: Signaling Transduction Pathways Of the At1 Receptormentioning

confidence: 99%

The angiotensin II type 1 receptor and receptor-associated proteins

et al. 2001

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“…Cell Culture-Rat aortic VSMC were maintained in DMEM supplemented with 10% (v/v) fetal bovine serum, 10 mg/ml streptomycin, and 100 units/ml penicillin at 37°C in a 5% CO 2 enriched, humidified atmosphere as we have previously described (1,2,5,6). Cells from passages 5 and 6 were routinely subcultured 1:5 or 1:10 at 7-day intervals, and the medium was changed at 2-3-day intervals.…”

Section: Methodsmentioning

confidence: 99%

Role of Janus Kinase/Signal Transducer and Activator of Transcription and Mitogen-activated Protein Kinase Cascades in Angiotensin II- and Platelet-derived Growth Factor-induced Vascular Smooth Muscle Cell Proliferation

Marrero

Schieffer

et al. 1997

Journal of Biological Chemistry

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In vascular smooth muscle cells, the induction of early growth response genes involves the Janus kinase (JAK)/ signal transducer and activators of transcription (STAT) and the Ras/Raf-1/mitogen-activated protein kinase cascades. In the present study, we found that electroporation of antibodies against MEK1 or ERK1 abolished vascular smooth muscle cell proliferation in response to either platelet-derived growth factor or angiotensin II. However, anti-STAT1 or -STAT3 antibody electroporation abolished proliferative responses only to angiotensin II and not to platelet-derived growth factor. AG-490, a specific inhibitor of the JAK2 tyrosine kinase, prevented proliferation of vascular smooth muscle cells, complex formation between JAK2 and Raf-1, the tyrosine phosphorylation of Raf-1, and the activation of ERK1 in response to either angiotensin II or platelet-derived growth factor. However, AG-490 had no effect on angiotensin II-or platelet-derived growth factor-induced Ras/Raf-1 complex formation. Our results indicate that: 1) STAT proteins play an essential role in angiotensin II-induced vascular smooth muscle cell proliferation, 2) JAK2 plays an essential role in the tyrosine phosphorylation of Raf-1, and 3) convergent mitogenic signaling cascades involving the cytosolic kinases JAK2, MEK1, and ERK1 mediate vascular smooth muscle cell proliferation in response to both growth factor and G protein-coupled receptors.Previous work by our laboratory (1-6) on cultured rat aortic vascular smooth muscle cells (VSMC) 1 and phenotypically similar glomerular mesangial cells has shown that protein tyrosine phosphorylation plays a critical role in angiotensin II (Ang II)-mediated intracellular signaling cascades. This is true despite the fact that G protein-coupled receptors in general and the Ang II AT 1 receptor in particular possess no intrinsic tyrosine kinase activity. It is also now recognized that Ang II can act not only as a vasoactive peptide but also as a growth factor. In particular, Ang II has been shown to stimulate proliferative and hypertrophic growth in VSMC, glomerular mesangial cells, cardiac fibroblasts, and myocytes via AT 1 receptor binding (4, 7-9). Like classic growth factors (e.g. platelet-derived growth factor (PDGF) and epidermal growth factor) and some cytokines (e.g. interferons and interleukins) (4, 8 -10), Ang II is also capable of stimulating a rapid increase in the mRNA levels of c-fos, an early growth response gene implicated in VSMC proliferation (4,7,8). However, the Ang II-stimulated intracellular signaling cascades responsible for c-fos induction and therefore proliferation in VSMC have not been well defined.One candidate mitogenic signaling cascade involves the activation of the small GTP-binding protein, Ras, which is traditionally mediated via classic growth factor receptors (4). Ras activation promotes the formation of a membrane-bound complex with Raf-1 (a serine/threonine protein kinase). Subsequent tyrosine phosphorylation of Raf-1 leads to its activation and the sequential stimulati...

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“…Immunoprecipitated proteins were separated by SDS-polyacrylamide gel electrophoresis, transferred to nitrocellulose by electroblotting, and probed with anti-PLC␥1 or anti-phosphotyrosine antibody as described previously (5,6).…”

Section: Methodsmentioning

confidence: 99%

Angiotensin II-induced Association of Phospholipase Cγ1 with the G-protein-coupled AT1 Receptor

Venema

et al. 1998

Journal of Biological Chemistry

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101

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An early event in signaling by the G-protein-coupled angiotensin II (Ang II) AT 1 receptor in vascular smooth muscle cells is the tyrosine phosphorylation and activation of phospholipase C␥1 (PLC␥1). In the present study, we show that stimulation of this event by Ang II in vascular smooth muscle cells is accompanied by binding of PLC␥1 to the AT 1 receptor in an Ang II-and tyrosine phophorylation-dependent manner. The PLC␥1-AT 1 receptor interaction appears to depend on phosphorylation of tyrosine 319 in a YIPP motif in the C-terminal intracellular domain of the AT 1 receptor and binding of the phosphorylated receptor by the most C-terminal of two Src homology 2 domains in PLC␥1. PLC␥1 thus binds to the same site in the receptor previously identified for binding by the SHP-2 phosphotyrosine phosphatase⅐JAK2 tyrosine kinase complex. A single site in the C-terminal tail of the AT 1 receptor can, therefore, be bound in a ligand-dependent manner by two different downstream effector proteins. These data demonstrate that G-protein-coupled receptors can physically associate with intracellular proteins other than G proteins, creating membrane-delimited signal transduction complexes similar to those observed for classic growth factor receptors.Growth factor receptors belong to a family of receptors that contain an extracellular ligand binding domain, a single transmembrane portion, and a large intracellular tyrosine kinase catalytic domain. Ligand-induced receptor autophosphorylation promotes the interaction of the intracellular domains of the receptors with a number of downstream effector proteins or enzymes. Typically, these proteins contain one or more domains known as Src homology 2 (SH2) 1 domains. Among these SH2 domain-containing proteins are phosphoinositide-specific phospholipase C␥ (PLC␥), the 85-kDa subunit of phosphatidylinositol 3-kinase, GTPase-activating proteins, growth factor receptor binding protein 2, the phosphotyrosine phosphatase SHP-2, and members of the nonreceptor Src family of tyrosine kinases (1, 2). Autophosphorylation of growth factor receptors occurs on defined tyrosine residues. These phosphorylated residues function to initiate cellular signaling cascades by acting as high affinity binding sites for the SH2 domains of various effector proteins. The selectivity of the receptor-effector interaction is determined, not only by the phosphorylated tyrosine residue in the receptor but also by the three amino acids Cterminal to the phosphorylated tyrosine and by the structure of the SH2 domain of the interacting protein. For example, one of the identified sites for binding of the SH2 domains of PLC␥1 to the platelet-derived growth factor ␣ and ␤ receptors is a YIPP motif present in the receptors at residues 1018 -1021 and 1021-1024, respectively. Phosphorylation of tyrosines 1018 and 1021 in these motifs promotes binding of PLC␥1 to the platelet-derived growth factor receptor and tyrosine phosphorylation and activation of the enzyme (3, 4).Another family of cell surface receptors are the G-protein...

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Electroporation of pp60c− Antibodies Inhibits the Angiotensin II Activation of Phospholipase C-γ1 in Rat Aortic Smooth Muscle Cells

Cited by 169 publications

References 23 publications

The angiotensin II type 1 receptor and receptor-associated proteins

The angiotensin II type 1 receptor and receptor-associated proteins

Role of Janus Kinase/Signal Transducer and Activator of Transcription and Mitogen-activated Protein Kinase Cascades in Angiotensin II- and Platelet-derived Growth Factor-induced Vascular Smooth Muscle Cell Proliferation

Angiotensin II-induced Association of Phospholipase Cγ1 with the G-protein-coupled AT1 Receptor

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