Receptor and nonreceptor tyrosine kinases in vascular biology of hypertension

2010 ◽  
Vol 19 (2) ◽  
pp. 169-176 ◽  
Author(s):  
Alvaro Yogi ◽  
Sarah E OʼConnor ◽  
Glaucia E Callera ◽  
Rita C Tostes ◽  
Rhian M Touyz
Keyword(s):  
Tyrosine Kinases ◽  
Vascular Biology ◽  
Nonreceptor Tyrosine Kinases

Abstract P153: Role of Nonreceptor Tyrosine Kinases in Cardiac Fibrosis in a Mouse Model of Pressure Overload Hypertrophy

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Sundaravadivel Balasubramanian ◽  
Harinath Kasiganesan ◽  
Lakeya Quinones ◽  
Yuhua Zhang ◽  
Amy Bradshaw ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Heart Diseases ◽  
Pressure Overload ◽  
In Vivo Studies ◽  
Survival Pathways ◽  
And Function ◽  
Nonreceptor Tyrosine Kinases

During prolonged hypertrophic insult to the myocardium, while the function of cardiomyocytes needs to be protected, the hyperactivation of cardiac fibroblasts has to be curbed to prevent fibrosis. Previously, we showed that integrin-mediated non-receptor tyrosine kinase (NRTK) activation is required for normal functioning of both cardiac fibroblasts and cardiomyocytes. We hypothesized that inhibition of NRTKs in cardiac fibroblasts without affecting cardiomyocytes would be beneficial to the stressed myocardium. Our initial studies using kinase inactive forms of Src, Pyk2 and FAK expressed adenovirally in isolated primary cardiac fibroblasts showed that the pro-fibrotic signaling events as studied by fibronectin and collagen deposition are downregulated. Our in vivo studies in mouse transverse aortic constriction (TAC) model suggest that dasatinib, a multikinase NRTK inhibitor administration via a peritoneally implanted mini-osmotic pump is able to preserve ventricular geometry and function and reduce the accumulation of fibrotic extracellular matrix (ECM) proteins upon 4 wk pressure overload. Data obtained from cell culture experiments with kinase inactive NRTKs and dasatinib suggest that NRTK inhibition is able to reduce the proliferation, migration and mitogenic signaling in cardiac fibroblasts without affecting the cell survival pathways in cardiomyocytes. These data indicate that NRTKs play a significant pro-fibrotic role in cardiac fibroblasts and curbing the activity of NRTKs could be a potential therapeutic approach to treat fibrosis in hypertrophic heart diseases.

scholarly journals Two Distinct Phosphorylation Pathways Have Additive Effects on Abl Family Kinase Activation

2003 ◽  
Vol 23 (11) ◽  
pp. 3884-3896 ◽  
Author(s):  
Keith Q. Tanis ◽  
Darren Veach ◽  
Henry S. Duewel ◽  
William G. Bornmann ◽  
Anthony J. Koleske
Keyword(s):  
Tyrosine Kinases ◽  
Kinase Activity ◽  
Intramolecular Interactions ◽  
Activation Loop ◽  
Additive Effects ◽  
Nonreceptor Tyrosine Kinase ◽  
Kinase Activation ◽  
Surface Receptors ◽  
Nonreceptor Tyrosine Kinases ◽  
Stimulation Of

ABSTRACT The activities of the related Abl and Arg nonreceptor tyrosine kinases are kept under tight control in cells, but exposure to several different stimuli results in a two- to fivefold stimulation of kinase activity. Following the breakdown of inhibitory intramolecular interactions, Abl activation requires phosphorylation on several tyrosine residues, including a tyrosine in its activation loop. These activating phosphorylations have been proposed to occur either through autophosphorylation by Abl in trans or through phosphorylation of Abl by the Src nonreceptor tyrosine kinase. We show here that these two pathways mediate phosphorylation at distinct sites in Abl and Arg and have additive effects on Abl and Arg kinase activation. Abl and Arg autophosphorylate at several sites outside the activation loop, leading to 5.2- and 6.2-fold increases in kinase activity, respectively. We also find that the Src family kinase Hck phosphorylates the Abl and Arg activation loops, leading to an additional twofold stimulation of kinase activity. The autoactivation pathway may allow Abl family kinases to integrate or amplify cues relayed by Src family kinases from cell surface receptors.

Cardioprotection involves activation of NF-κB via PKC-dependent tyrosine and serine phosphorylation of IκB-α

2003 ◽  
Vol 285 (4) ◽  
pp. H1753-H1758 ◽  
Author(s):  
Jun Zhang ◽  
Peipei Ping ◽  
Thomas M. Vondriska ◽  
Xian-Liang Tang ◽  
Guang-Wu Wang ◽  
...  
Keyword(s):  
Ischemic Preconditioning ◽  
Tyrosine Kinases ◽  
Molecular Mechanisms ◽  
Coronary Occlusion ◽  
Kinase Inhibitor ◽  
Serine Phosphorylation ◽  
Inhibitory Protein ◽  
Nonreceptor Tyrosine Kinase ◽  
Pkc Inhibitor ◽  
Nonreceptor Tyrosine Kinases

Previous studies indicated that activation of PKC and Src tyrosine kinases by ischemic preconditioning (PC) may participate in the activation of NF-κB. However, the molecular mechanisms underlying activation of NF-κB during ischemic PC remain unknown. In the hearts of conscious rabbits, it was found that ischemic PC (6 cycles of 4-min coronary occlusion and 4-min reperfusion) significantly induced both tyrosine (+226.9 ± 42%) and serine (+137.0 ± 36%) phosphorylation of the NF-κB inhibitory protein IκB-α, concomitant with increased activation of the IκB-α kinases IKKα (+255.0 ± 46%) and IKKβ (+173.1 ± 35%). Furthermore, both tyrosine and serine phosphorylation of IκB-α were blocked by pretreatment with either the nonreceptor tyrosine kinase inhibitor lavendustin-A (LD-A) or the PKC inhibitor chelerythrine (Che) (both given at doses previously shown to block ischemic PC). Interestingly, Che completely abolished PC-induced activation of IKKα/β, whereas LD-A had no effect. In addition, IκB-α protein level did not change during ischemic PC. Together, these data indicate that ischemic PC-induced activation of NF-κB occurs through both tyrosine and serine phosphorylation of IκB-α and is regulated by nonreceptor tyrosine kinases and PKC.

Osmotic shrinkage elicits FAK- and Src phosphorylation and Src-dependent NKCC1 activation in NIH3T3 cells

2015 ◽  
Vol 308 (2) ◽  
pp. C101-C110 ◽  
Author(s):  
Line Jee Hartmann Rasmussen ◽  
Helene Steenkær Holm Müller ◽  
Bente Jørgensen ◽  
Stine Falsig Pedersen ◽  
Else Kay Hoffmann
Keyword(s):  
Focal Adhesion ◽  
Tyrosine Kinases ◽  
Volume Regulation ◽  
Mammalian Cells ◽  
Myosin Light Chain ◽  
Janus Kinase ◽  
Nih3t3 Cells ◽  
Src Inhibitor ◽  
Nonreceptor Tyrosine Kinases

The mechanisms linking cell volume sensing to volume regulation in mammalian cells remain incompletely understood. Here, we test the hypothesis that activation of nonreceptor tyrosine kinases Src, focal adhesion kinase (FAK), and Janus kinase-2 (Jak2) occurs after osmotic shrinkage of NIH3T3 fibroblasts and contributes to volume regulation by activation of NKCC1. FAK phosphorylation at Tyr397, Tyr576/577, and Tyr861 was increased rapidly after exposure to hypertonic (575 mOsm) saline, peaking after 10 (Tyr397, Tyr576/577) and 10–30 min (Tyr861). Shrinkage-induced Src family kinase autophosphorylation (pTyr416-Src) was induced after 2–10 min, and immunoprecipitation indicated that this reflected phosphorylation of Src itself, rather than Fyn and Yes. Phosphorylated Src and FAK partly colocalized with vinculin, a focal adhesion marker, after hypertonic shrinkage. The Src inhibitor pyrazolopyrimidine-2 (PP2, 10 μM) essentially abolished shrinkage-induced FAK phosphorylation at Tyr576/577 and Tyr861, yet not at Tyr397, and inhibited shrinkage-induced NKCC1 activity by ∼50%. The FAK inhibitor PF-573,228 augmented shrinkage-induced Src phosphorylation, and inhibited shrinkage-induced NKCC1 activity by ∼15%. The apparent role of Src in NKCC1 activation did not reflect phosphorylation of myosin light chain kinase (MLC), which was unaffected by shrinkage and by PP2, but may involve Jak2, a known target of Src, which was rapidly activated by osmotic shrinkage and inhibited by PP2. Collectively, our findings suggest a major role for Src and possibly the Jak2 axis in shrinkage-activation of NKCC1 in NIH3T3 cells, whereas no evidence was found for major roles for FAK and MLC in this process.

scholarly journals Cell Regulation by Phosphotyrosine-Targeted Ubiquitin Ligases

2015 ◽  
Vol 35 (11) ◽  
pp. 1886-1897 ◽  
Author(s):  
Jonathan A. Cooper ◽  
Tomonori Kaneko ◽  
Shawn S. C. Li
Keyword(s):  
Tyrosine Kinases ◽  
Cell Biology ◽  
Relevant Literature ◽  
Ubiquitin Ligases ◽  
Endocrine Disorders ◽  
Biological Functions ◽  
Tyrosine Kinase Signaling ◽  
E3 Ligases ◽  
Recent Developments ◽  
Nonreceptor Tyrosine Kinases

Three classes of E3 ubiquitin ligases, members of the Cbl, Hakai, and SOCS-Cul5-RING ligase families, stimulate the ubiquitination of phosphotyrosine-containing proteins, including receptor and nonreceptor tyrosine kinases and their phosphorylated substrates. Because ubiquitination frequently routes proteins for degradation by the lysosome or proteasome, these E3 ligases are able to potently inhibit tyrosine kinase signaling. Their loss or mutational inactivation can contribute to cancer, autoimmunity, or endocrine disorders, such as diabetes. However, these ligases also have biological functions that are independent of their ubiquitination activity. Here we review relevant literature and then focus on more-recent developments in understanding the structures, substrates, and pathways through which the phosphotyrosine-specific ubiquitin ligases regulate diverse aspects of cell biology.

scholarly journals The Thrombopoietin Receptor Can Mediate Proliferation without Activation of the Jak-STAT Pathway

1997 ◽  
Vol 186 (12) ◽  
pp. 1947-1955 ◽  
Author(s):  
Marion Dorsch ◽  
Pang-Dian Fan ◽  
Nika N. Danial ◽  
Paul B. Rothman ◽  
Stephen P. Goff
Keyword(s):  
Tyrosine Kinases ◽  
Kinase Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Signal Transducers ◽  
Thrombopoietin Receptor ◽  
Mitogen Activated Protein ◽  
Mutant Receptors ◽  
Nonreceptor Tyrosine Kinases ◽  
Stat Pathway

Cytokine receptors of the hematopoietic receptor superfamily lack intrinsic tyrosine kinase domains for the intracellular transmission of their signals. Instead all members of this family associate with Jak family nonreceptor tyrosine kinases. Upon ligand stimulation of the receptors, Jaks are activated to phosphorylate target substrates. These include STAT (signal transducers and activators of transcription) proteins, which after phosphorylation translocate to the nucleus and modulate gene expression. The exact role of the Jak-STAT pathway in conveying growth and differentiation signals remains unclear. Here we describe a deletion mutant of the thrombopoietin receptor (c-mpl) that has completely lost the capacity to activate Jaks and STATs but retains its ability to induce proliferation. This mutant still mediates TPO-induced phosphorylation of Shc, Vav, mitogen-activated protein kinase (MAPK) and Raf-1 as well as induction of c-fos and c-myc, although at somewhat reduced levels. Furthermore, we show that both wild-type and mutant receptors activate phosphatidylinositol (PI) 3-kinase upon thrombopoietin stimulation and that thrombopoietin-induced proliferation is inhibited in the presence of the PI 3-kinase inhibitor wortmannin. These results demonstrate that the Jak-STAT pathway is dispensable for the generation of mitogenic signals by a cytokine receptor.

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