scholarly journals Role of exon-16-deleted HER2 in breast carcinomas

2006 ◽  
Vol 13 (1) ◽  
pp. 221-232 ◽  
Author(s):  
F Castiglioni ◽  
E Tagliabue ◽  
M Campiglio ◽  
S M Pupa ◽  
A Balsari ◽  
...  
Keyword(s):  
Splice Variant ◽  
Kinase Domain ◽  
Critical Threshold ◽  
Tyrosine Kinase Domain ◽  
Her Family ◽  
Therapeutic Drugs ◽  
Extracellular Region ◽  
Her2 Mrna ◽  
Low Sensitivity

A splice variant of the human gene HER2, lacking exon-16 (ΔHER2) which encodes a small extracellular region, has been described. This altered receptor forms disulfide bond-stabilized homodimers. We report here that the ΔHER2 splice variant represents about 9% of the HER2 mRNA obtained from most of the 46 breast carcinoma samples with HER2 expression levels ranging from 3+ to 0 by HercepTest. Analysis of human cells transfected with ΔHER2 or wild-type (WT) cDNA revealed no growth of WT cells in nude mice, whereas clones expressing 10-fold less ΔHER2 were tumorigenic. Unlike WT transfectants, ΔHER2-expressing cells showed low sensitivity to two new therapeutic drugs targeting receptors of the HER family (ZD1839 and Trastuzumab), whereas an inhibitor of the HER2 tyrosine kinase domain (Emodin) blocked activation of both ΔHER2 and WT transfectants. Taken together, our findings indicate that the ΔHER2 transcript encodes the transforming form of the oncoprotein. It is plausible that malignant transformation arises when a critical threshold of ΔHER2 is reached in HER2-overexpressing tumors. Specific inhibitors of HER2 catalytic activity represent a promising approach to therapy of HER2-overexpressing tumors.

scholarly journals Regulation of Jak2 Function by Phosphorylation of Tyr317 and Tyr637 during Cytokine Signaling

2009 ◽  
Vol 29 (12) ◽  
pp. 3367-3378 ◽  
Author(s):  
Scott A. Robertson ◽  
Rositsa I. Koleva ◽  
Lawrence S. Argetsinger ◽  
Christin Carter-Su ◽  
Jarrod A. Marto ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Activity ◽  
Feedback Inhibition ◽  
Dominant Role ◽  
Kinase Domain ◽  
Cytokine Signaling ◽  
Tyrosine Kinase Domain ◽  
Phosphorylation Sites ◽  
Cytokine Stimulation

ABSTRACT Jak2, the cognate tyrosine kinase for numerous cytokine receptors, undergoes multisite phosphorylation during cytokine stimulation. To understand the role of phosphorylation in Jak2 regulation, we used mass spectrometry to identify numerous Jak2 phosphorylation sites and characterize their significance for Jak2 function. Two sites outside of the tyrosine kinase domain, Tyr317 in the FERM domain and Tyr637 in the JH2 domain, exhibited strong regulation of Jak2 activity. Mutation of Tyr317 promotes increased Jak2 activity, and the phosphorylation of Tyr317 during cytokine signaling requires prior activation loop phosphorylation, which is consistent with a role for Tyr317 in the feedback inhibition of Jak2 kinase activity after receptor stimulation. Comparison to several previously identified regulatory phosphorylation sites on Jak2 revealed a dominant role for Tyr317 in the attenuation of Jak2 signaling. In contrast, mutation of Tyr637 decreased Jak2 signaling and activity and partially suppressed the activating JH2 V617F mutation, suggesting a role for Tyr637 phosphorylation in the release of JH2 domain-mediated suppression of Jak2 kinase activity during cytokine stimulation. The phosphorylation of Tyr317 and Tyr637 act in concert with other regulatory events to maintain appropriate control of Jak2 activity and cytokine signaling.

Abstract 677: The Role of Discoidin Domain Receptor 1 in Vascular Calcification in Atherosclerosis and Diabetes

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Marsel Lino ◽  
Michelle P Bendeck
Keyword(s):  
Signaling Pathway ◽  
Vascular Calcification ◽  
Kinase Domain ◽  
Plaque Burden ◽  
Tyrosine Kinase Domain ◽  
Discoidin Domain Receptor ◽  
Related Transcription Factor ◽  
Discoidin Domain Receptor 1

Background: Atherosclerosis and diabetes share many common pathogenic mechanisms. Vascular calcification is a common and severe complication in patients with atherosclerosis and type-2 diabetes (T2D), and occurs when vascular smooth muscle cells (VSMCs) trans-differentiate into osteoblast-like cells, in a process driven by runt-related transcription factor-2 (RUNX2). Our laboratory has recently discovered that Discoidin Domain Receptor-1 (DDR1) deletion reduces vascular calcification in vivo in Ldlr -/- mice. Additionally, we have shown that RUNX2 activity is reduced in Ddr1 -/- VSMCs. However, little is known about the mechanism by which DDR1 mediates calcification and RUNX2 activity. Rationale: The insulin signaling pathway plays an important role in T2D and VSMC function. It has recently been discovered that PI3K binds to the DDR1 tyrosine kinase domain upon DDR1 activation. Hypothesis: DDR1 promotes vascular calcification by inducing RUNX2 activity via the PI3K/Akt signaling pathway in T2D. Methods/Results: To study the role of DDR1 in vascular calcification in T2D, Ldlr -/- (SKO) and Ldlr-/-; Ddr1 -/- (DKO) mice were placed on a modified Western diet (40% fat, 43% carbohydrates, 0.5% cholesterol) for 12 weeks. Oil Red-O staining of the descending aorta showed reduced plaque burden in DKO mice (9.1±2.7% vs 4.4±2.9% surface area; p<0.05). Measurements of vascular calcification are ongoing. To determine the mechanism by which DDR1 modulates VSMC calcification, primary VSMCs collected from Ddr1 +/+ and DDR1 -/- mice were cultured in osteogenic media for 12 days to induce calcification. Proliferation and calcification were significantly reduced in DDR1 -/- VSMCs. Additionally, DDR1 -/- VSMCs showed significantly reduced p-Akt levels when stimulated with insulin. Significance: Current treatments for vascular calcification are non-specific and often pose a risk to bone health. This is the first study to test the role of DDR1 in vascular calcification in an animal model of T2D, which will provide novel insight into the mechanism of vascular calcification and uncover new potential therapeutic approaches.

Two FGF-receptor homologues of Drosophila: one is expressed in mesodermal primordium in early embryos

Development ◽  
1993 ◽  
Vol 117 (2) ◽  
pp. 751-761 ◽  
Author(s):  
E. Shishido ◽  
S. Higashijima ◽  
Y. Emori ◽  
K. Saigo
Keyword(s):  
Kinase Domain ◽  
Precursor Cells ◽  
Molecular Structures ◽  
Tyrosine Kinase Domain ◽  
Receptor System ◽  
Fgf Receptor ◽  
Extracellular Region ◽  
Early Embryos ◽  
Snail Proteins ◽  
Cns Midline

The fibroblast growth factor (FGF)/receptor system is thought to mediate various developmental events in vertebrates. We examined molecular structures and expression of DFR1 and DFR2, two Drosophila genes closely related to vertebrate FGF-receptor genes. DFR1 and DFR2 proteins contain two and five immunoglobulin-like domains, respectively, in the extracellular region, and a split tyrosine kinase domain in the intracellular region. In early embryos, DFR1 RNA expression, requiring both twist and snail proteins, is specific to mesodermal primordium and invaginated mesodermal cells. At later stages, putative muscle precursor cells and cells in the central nervous system (CNS) express DFR1. DFR2 expression occurs in endodermal precursor cells, CNS midline cells and certain ectodermal cells such as those of trachea and salivary duct. FGF-receptor homologues in Drosophila would thus appear essential for generation of mesodermal and endodermal layers, invaginations of various types of cells, and CNS formation.

Quantitative accuracy of serotonergic neurotrans-mission imaging with high-resolution 123I SPECT

2004 ◽  
Vol 43 (06) ◽  
pp. 185-189 ◽  
Author(s):  
J. T. Kuikka
Keyword(s):  
High Resolution ◽  
Scatter Correction ◽  
Region Of Interest ◽  
Binding Potential ◽  
Partial Volume ◽  
Therapeutic Drugs ◽  
Quantitative Accuracy ◽  
Critical Error ◽  
Statistical Noise

Summary Aim: Serotonin transporter (SERT) imaging can be used to study the role of regional abnormalities of neurotransmitter release in various mental disorders and to study the mechanism of action of therapeutic drugs or drugs’ abuse. We examine the quantitative accuracy and reproducibility that can be achieved with high-resolution SPECT of serotonergic neurotransmission. Method: Binding potential (BP) of 123I labeled tracer specific for midbrain SERT was assessed in 20 healthy persons. The effects of scatter, attenuation, partial volume, mis-registration and statistical noise were estimated using phantom and human studies. Results: Without any correction, BP was underestimated by 73%. The partial volume error was the major component in this underestimation whereas the most critical error for the reproducibility was misplacement of region of interest (ROI). Conclusion: The proper ROI registration, the use of the multiple head gamma camera with transmission based scatter correction introduce more relevant results. However, due to the small dimensions of the midbrain SERT structures and poor spatial resolution of SPECT, the improvement without the partial volume correction is not great enough to restore the estimate of BP to that of the true one.

NIDDM associated with mutation in tyrosine kinase domain of insulin receptor gene

Diabetes ◽  
1992 ◽  
Vol 41 (4) ◽  
pp. 521-526 ◽  
Author(s):  
S. Cocozza ◽  
A. Porcellini ◽  
G. Riccardi ◽  
A. Monticelli ◽  
G. Condorelli ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Insulin Receptor ◽  
Receptor Gene ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Insulin Receptor Gene

Plasma therapy a possible hope to fight against COVID-19

2020 ◽  
Author(s):  
Ravikant Piyush ◽  
Aroni Chatterjee ◽  
Shashikant Ray
Keyword(s):  
Middle East ◽  
Severe Acute Respiratory Syndrome ◽  
Viral Disease ◽  
Plasma Therapy ◽  
Therapeutic Drugs ◽  
Wild Fire ◽  
The World ◽  
Short Span ◽  
Game Changer

The world is currently going through a disastrous event and a catastrophic upheaval caused by the coronavirus disease 2019 (COVID-19). The pandemic has resulted in loss of more than 150000 deaths across the globe. Originating from China and spreading across all continents within a short span of time, it has become a matter of international emergency. Different agencies are adopting diverse approaches to stop and spread of this viral disease but still now nothing confirmatory has come up. Due to lack of vaccines and proper therapeutic drugs, the disease is still spreading like wild fire without control. An Old but very promising method- the convalescent plasma therapy could be the key therapy to stop this pandemic. This method has already proven its mettle on several occasions previously and has been found to be effective in curing the pandemics induced by Ebola, severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) belongs to the same group of β-Coronavirus that has resulted in the above diseases. Therefore, the role of plasma therapy is being explored for treatment of this disease. In this review, we have mainly focused on the role of convalescent plasma therapy and why its use should be promoted in fight against COVID-19, as it could turn out to be a game changer.

Impaired Angiogenesis in Systemic Sclerosis: The Emerging Role of the Antiangiogenic VEGF165b Splice Variant

2011 ◽  
Vol 21 (7) ◽  
pp. 204-210 ◽  
Author(s):  
Mirko Manetti ◽  
Serena Guiducci ◽  
Lidia Ibba-Manneschi ◽  
Marco Matucci-Cerinic
Keyword(s):  
Systemic Sclerosis ◽  
Splice Variant ◽  
Impaired Angiogenesis
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