Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin II (AII), acting via its G-protein linked receptor, is an important regulator of cardiac, vascular, and renal function. Following injection of AII into rats, we find that there is also a rapid tyrosine phosphorylation of the major insulin receptor substrates 1 and 2 (IRS-1 and IRS-2) in the heart. This phenomenon appears to involve JAK2 tyrosine kinase, which associates with the AT1 receptor and IRS-1/IRS-2 after AII stimulation. AII-induced phosphorylation leads to binding of phosphatidylinositol 3-kinase (PI 3-kinase) to IRS-1 and IRS-2; however, in contrast to other ligands, AII injection results in an acute inhibition of both basal and insulin-stimulated PI 3-kinase activity. The latter occurs without any reduction in insulin receptor or IRS phosphorylation or in the interaction of the p85 and p110 subunits of PI 3-kinase with each other or with IRS-1/IRS-2. These effects of AII are inhibited by AT1 receptor antagonists. Thus, there is direct cross-talk between insulin and AII signaling pathways at the level of both tyrosine phosphorylation and PI 3-kinase activation. These interactions may play an important role in the association of insulin resistance, hypertension, and cardiovascular disease.
...
PMID:Cross-talk between the insulin and angiotensin signaling systems. 890 9

This study was designed to determine whether the JAK/STAT (indicating just another kinase/signal transducer and activator of transcription) pathway is activated in cardiac hypertrophy induced in vivo by pressure overload in rats and to demonstrate whether angiotensin II is involved in the activation of the JAK/STAT pathway. Acute pressure overload was produced by constricting the abdominal aorta of Wistar rats. Immunoprecipitation-Western blot analysis revealed that pressure overload activated JAK1, JAK2, and Tyk2 as early as 5 minutes and that STAT1, STAT2, and STAT3 were tyrosine-phosphorylated rapidly after exposure to the pressure overload. Phosphorylation of STAT1 and STAT2 peaked in the early stage at 5 to 15 minutes, whereas that of STAT3 peaked in the late stage at 60 minutes. Gel mobility shift of the interferon gamma activation site/interferon alpha-stimulating response element was observed immediately after the aortic banding, whereas the band of sis-inducing element was shifted in the late stage at 60 minutes. Both cilazapril (angiotensin II-converting enzyme inhibitor) and E4177 (angiotensin II type 1 [AT1] receptor antagonist) significantly suppressed the phosphorylation of Tyk2 and partially inhibited the phosphorylation of JAK2, but neither affected JAK1. Coimmunoprecipitation of the AT1 receptor with JAK2 or Tyk2 was clearly observed at 5 minutes and peaked at 15 minutes (20-fold the control value). These results indicate that the JAK/STAT pathway is activated by acute pressure overload in rats and that angiotensin II is involved in activating Tyk2, and partially activating JAK2, via the AT1 receptor. Both angiotensin II-dependent and -independent pathways take part in activating the JAK/STAT pathway in the pressure-overloaded rat heart.
...
PMID:Role of angiotensin II in activation of the JAK/STAT pathway induced by acute pressure overload in the rat heart. 931 43

An early event in signaling by the G-protein-coupled angiotensin II (Ang II) AT1 receptor in vascular smooth muscle cells is the tyrosine phosphorylation and activation of phospholipase Cgamma1 (PLCgamma1). In the present study, we show that stimulation of this event by Ang II in vascular smooth muscle cells is accompanied by binding of PLCgamma1 to the AT1 receptor in an Ang II- and tyrosine phophorylation-dependent manner. The PLCgamma1-AT1 receptor interaction appears to depend on phosphorylation of tyrosine 319 in a YIPP motif in the C-terminal intracellular domain of the AT1 receptor and binding of the phosphorylated receptor by the most C-terminal of two Src homology 2 domains in PLCgamma1. PLCgamma1 thus binds to the same site in the receptor previously identified for binding by the SHP-2 phosphotyrosine phosphatase.JAK2 tyrosine kinase complex. A single site in the C-terminal tail of the AT1 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.
...
PMID:Angiotensin II-induced association of phospholipase Cgamma1 with the G-protein-coupled AT1 receptor. 951 77

The accumulation and organization of extracellular matrix (ECM) components play critical roles in development, maintenance, and pathogenesis of most organ systems. These processes are regulated by the precisely orchestrated expression of ECM components, their receptors, and matrix proteases. The collagen gel culture system has been extensively used as a model to examine ECM remodeling similar to that which occurs during development and wound healing. Growth factors, including transforming growth factor-beta, platelet-derived growth factor, insulin-like growth factor, and angiotensin II, have been shown to stimulate collagen gel contraction. The present studies were undertaken to begin to examine the mechanisms through which angiotensin II stimulates collagen remodeling and gel contraction. These studies indicate that angiotensin II stimulates collagen gel contraction by isolated heart fibroblasts in a dose-dependent manner and that this response is inhibited by the AT1 receptor antagonist Losartan. Furthermore, stimulation of collagen gel contraction by angiotensin II is also blocked by the src-related tyrosine kinase inhibitors genistein and herbimycin, indicating that activation of tyrosine kinases plays critical roles in this process. Stimulation of gel contraction by angiotensin II also involves the activation of JAK2, a member of the JAK/STAT pathways of transcriptional activation. Immunoprecipitation of surface-labeled fibroblasts indicate that cell surface levels of collagen-binding integrins also increase in response to angiotensin II treatment. Determining the underlying mechanisms regulating ECM remodeling is essential to understanding the role of ECM organization in development and disease.
...
PMID:Angiotensin II-stimulated collagen gel contraction by heart fibroblasts: role of the AT1 receptor and tyrosine kinase activity. 976 19

Angiotensin II (Ang II) induces vascular smooth muscle cell (VSMC) growth by activating Gq-protein-coupled AT1 receptors, which leads to elevation of cytosolic Ca2+ ([Ca2+]i) and activation of protein kinase C (PKC) and mitogen-activated protein kinases. To assess the link between these Ang II-induced signaling events, we examined the effect of Ang II on the proline-rich tyrosine kinase (PYK2), previously found to be activated by a variety of stimuli that increase [Ca2+]i or activate PKC. PYK2 distribution was demonstrated in rat aortic tissue and in cultured VSMC by immunohistochemistry, revealing a cytosolic distribution distinct from smooth muscle alpha-actin, focal adhesion kinase, or paxillin. The involvement of PYK2 in Ang II signaling was measured by immunoprecipitation and immune complex kinase assays. Treatment of quiescent VSMC with Ang II resulted in a concentration- and time-dependent increase in PYK2 tyrosine phosphorylation and kinase activity in PYK2 immunoprecipitates. PYK2 phosphorylation was inhibited by AT1 receptor blockade and was attenuated by downregulation of PKC or the chelation of [Ca2+]i. Treatment with either phorbol ester or Ca2+ ionophore also increased PYK2 phosphorylation, suggesting that PKC activation and/or increased [Ca2+]i are both necessary and sufficient to activate PYK2. Activation of PYK2 by Ang II was also associated with increased PYK2-src complex formation, suggesting that PYK2 activation represents a potential link between Ang II-stimulated [Ca2+]i and PKC activation with downstream signaling events such as mitogen-activated protein kinase activation involved in the regulation of VSMC growth.
...
PMID:Calcium- and protein kinase C-dependent activation of the tyrosine kinase PYK2 by angiotensin II in vascular smooth muscle. 977 31

Angiotensin II (Ang II) AT1 receptors on vascular smooth muscle cells (VSMCs) are coupled to the Janus-activated kinase (JAK)/signal transducers and activators of transcription (STAT) pathway. We have shown previously that Ang II stimulation of VSMCs results in the tyrosine phosphorylation of JAK2 and STAT1 and the translocation of STAT1 to the nucleus. In the present study, we demonstrate using specific enzyme inhibitors and antisense oligonucleotides that both JAK2 and p59 Fyn tyrosine kinases are required for the Ang II-induced tyrosine phosphorylation and nuclear translocation of STAT1 in VSMCs. Neither tyrosine kinase, however, appears to function upstream from the other in a phosphorylation cascade. Rather, p59 Fyn functions as an Ang II-activated docking protein for both JAK2 and STAT1, a docking interaction that may facilitate JAK2-mediated STAT1 tyrosine phosphorylation. In this study, we have also identified the nuclear dual-specificity phosphatase mitogen-activated protein kinase phosphatase 1 as the enzyme responsible for STAT1 tyrosine dephosphorylation in VSMCs.
...
PMID:Angiotensin II-induced tyrosine phosphorylation of signal transducers and activators of transcription 1 is regulated by Janus-activated kinase 2 and Fyn kinases and mitogen-activated protein kinase phosphatase 1. 980 57

Angiotensin II (ANG II) exerts its effects on vascular smooth muscle cells through G protein-coupled AT1 receptors. ANG II stimulation activates the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway by inducing tyrosine phosphorylation, activation, and association of JAK2 with the receptor. Association appears to be required for JAK2 phosphorylation. In the present study, electroporation experiments with neutralizing anti-Src homology phosphatase-1 (SHP-1) and anti-SHP-2 antibodies and time course determinations of SHP-1 and SHP-2 activation and complexation with JAK2 suggest that the tyrosine phosphatases, SHP-1 and SHP-2, have opposite roles in ANG II-induced JAK2 phosphorylation. SHP-1 appears responsible for JAK2 dephosphorylation and termination of the ANG II-induced JAK/STAT cascade. SHP-2 appears to have an essential role in JAK2 phosphorylation and initiation of the ANG II-induced JAK/STAT cascade leading to cell proliferation. The motif in the AT1 receptor that is required for association with JAK2 is also required for association with SHP-2. Furthermore, SHP-2 is required for JAK2-receptor association. SHP-2 may thus play a role as an adaptor protein for JAK2 association with the receptor, thereby facilitating JAK2 phosphorylation and activation.
...
PMID:Regulation of angiotensin II-induced JAK2 tyrosine phosphorylation: roles of SHP-1 and SHP-2. 981 69

Angiotensin II (Ang II) and basic fibroblast growth factor (bFGF) are important modulators of cell growth under physiological and pathophysiological conditions. We and others have previously shown that these growth factors increase insulin-like growth factor-1 receptor (IGF-1R) number and mRNA in vascular smooth muscle cells and that this effect is transcriptionally regulated. To study the mechanisms and the signaling pathways involved, IGF-1R promoter reporter constructs were transiently transfected in CHO-AT1 cells that overexpress angiotensin AT1 receptors. Our findings indicate that Ang II and bFGF significantly increased IGF-1R promoter activity up to 7- and 3-fold, respectively. The effect induced by Ang II was mediated via a tyrosine kinase-dependent mechanism, since tyrphostin A25 largely inhibited the Ang II-induced increase in promoter activity. In addition, co-transfection of dominant negative Ras, Raf, and MEK1 or pretreatment with the MEK inhibitor PD 98059 dose-dependently decreased both the Ang II- and bFGF-induced increase in IGF-1R transcription and protein expression, suggesting that the Ras-Raf-mitogen-activated protein kinase kinase pathway is required for both growth factors. Reactive oxygen species have been shown to act as second messengers in Ang II-induced signaling, and activation of the transcription factor NF-kappaB is redox-sensitive. While co-transfection of dominant negative IkappaBalpha mutant completely inhibited the Ang II-induced increase in transcription, it had no effect on the bFGF signaling. In contrast, co-transfection studies indicated that the transcription factors STAT1, STAT3, and c-Jun and the Janus kinase 2 kinase are required in the signaling pathway of bFGF, whereas only dominant c-Jun inhibited the Ang II-induced effect. In summary, these data demonstrate that Ang II and bFGF increase IGF-1R gene transcription via distinct as well as shared pathways and have important implications for understanding growth-stimulatory effects of these growth factors on vascular cells.
...
PMID:Distinct and common pathways in the regulation of insulin-like growth factor-1 receptor gene expression by angiotensin II and basic fibroblast growth factor. 992 Aug 98

-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.
...
PMID:Involvement of PYK2 in angiotensin II signaling of vascular smooth muscle cells. 993 Nov 5

This study was designed to determine whether mechanical stretch activates the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway in cardiomyocytes and, if so, by what mechanism. Neonatal rat/murine cardiomyocytes were cultured on malleable silicone dishes and were stretched by 20%. Mechanical stretch induced rapid phosphorylation of JAK1, JAK2, Tyk2, STAT1, STAT3, and glycoprotein 130 as early as 2 minutes and peaked at 5 to 15 minutes. It also caused gel mobility shift of sis-inducing element, which was supershifted by preincubation with anti-STAT3 antibody. Preincubation with CV11974 (AT1 blocker) partially inhibited the phosphorylation of STAT1, but not that of STAT3. Preincubation with TAK044 (endothelin-1-type A/B-receptor blocker) did not attenuate this pathway. RX435 (anti-glycoprotein 130 blocking antibody) inhibited the phosphorylation of STAT3 and partially inhibited that of STAT1. Phosphorylation of STAT1 and STAT3 was strongly inhibited by HOE642 (Na+/H+ exchanger inhibitor) and BAPTA-AM (intracellular calcium chelator), but not by gadolinium (stretch-activated ion channel inhibitor), EGTA (extracellular Ca2+ chelator), or KN62 (Ca2+/calmodulin kinase II inhibitor). Chelerythrine (protein kinase C inhibitor) partially inhibited the phosphorylation of STAT1 and STAT3. Mechanical stretch also augmented the mRNA expression of cardiotrophin-1, interleukin-6, and leukemia inhibitory factor at 60 to 120 minutes. These results indicated that the JAK/STAT pathway was activated by mechanical stretch, and that this activation was partially dependent on autocrine/paracrine-secreted angiotensin II and was mainly dependent on the interleukin-6 family of cytokines but was independent of endothelin-1. Moreover, certain levels of intracellular Ca2+ were necessary for stretch-induced activation of this pathway, and protein kinase C was also partially involved in this activation.
...
PMID:Mechanical stretch activates the JAK/STAT pathway in rat cardiomyocytes. 1034 87


1 2 3 4 5 6 7 8 9 10 Next >>

---