Tyrosine Kinase Receptor Research Papers (original) (raw)

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- Physiology, Aging, Gene expression, Brain
- by Giuseppe G M Leone
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- Leukemia, Stem Cell Transplantation, Acute Myeloid Leukemia, Mutation

Gastrointestinal stromal tumors (GIST) arising from interstitial cells of Cajal, represent the first type of solid tumor, which is very sensitive to a specific molecularly targeted tyrosine kinase receptor blocker (i. e., imatinib). On CT, which is considered as the reference technique, GISTs typically present as large, well-delineated, heterogeneous and sometimes exophytic masses. In contrast with the absence of lymph

- by Roland Rymer and +1
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- Computed Tomography, Positron Emission Tomography, Tyrosine Kinase Receptor, PET imaging

The neuromuscular junction is made up of the apposition of highly differentiated domains of three types of cell: the motor neuronal ending, the terminal Schwann cell and the muscle postsynaptic membrane. These three components are surrounded by a basal lamina, dedicated to molecular signal exchanges controlling neuromuscular formation, maturation and maintenance. This functional and structural differentiated complex conducts synaptic neurotransmission to the skeletal muscle fiber. Nerve and muscle have distinct roles in synaptic compartment differentiation. The initial steps of this differentiation and the motor endplate formation require several postsynaptic molecular agents including agrin, the tyrosine kinase receptor MuSK. Neuregulin is essentially involved in Schwann cell survival and guidance for axonal growth.

Targeted therapies for hematological malignancies have come of age since the advent of all trans retinoic acid (ATRA) for treating APL and STI571/Imatinib Mesylate/Gleevec for CML. There are good molecular targets for other malignancies and several new drugs are in clinical trials. In this review, we will concentrate on individual abnormalities that exist in the myelodysplastic syndromes (MDS) and myeloid leukemias that are targets for small molecule therapies (summarised in ). We will cover fusion proteins that are produced as a result of translocations, including BCR-ABL, the FLT3 tyrosine kinase receptor and RAS. Progression of diseases such as MDS to secondary AML occur as a result of changes in the balance between cell proliferation and apoptosis and we will review targets in both these areas, including reversal of epigenetic silencing of genes such as p15 INK4B .

- by Rose-ann Padua and +1
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- Clinical Trial, Gene Silencing, Cell Division, Acute Myeloid Leukemia

Risk assessment of individuals with anaphylaxis is currently hampered by lack of (1) an optimal and readily available laboratory test to confirm the clinical diagnosis of an anaphylaxis episode and (2) an optimal method of distinguishing allergensensitized individuals who are clinically tolerant from those at risk for anaphylaxis episodes after exposure to the relevant allergen. Our objectives were to review the effector mechanisms involved in the pathophysiology of anaphylaxis; to explore the possibility of developing an optimal laboratory test to confirm the diagnosis of an anaphylaxis episode, and the possibility of improving methods to distinguish allergen sensitization from clinical reactivity; and to develop a research agenda for risk assessment in anaphylaxis. Researchers from the American Academy of Allergy, Asthma & Immunology and the European Academy of Allergology and Clinical Immunology held a PRACTALL (Practical Allergy) meeting to discuss these objectives. New approaches being investigated to support the clinical diagnosis of anaphylaxis include serial measurements of total tryptase in serum during an anaphylaxis episode, and measurement of baseline total tryptase levels after the episode. Greater availability of the test for mature b-tryptase, a more specific mast cell activation marker for anaphylaxis than total tryptase, is needed. Measurement of chymase, mast cell carboxypeptidase A3, platelet-activating factor, and other mast cell products may prove to be useful. Consideration should be given to measuring a panel of mediators from mast cells and basophils. New approaches being investigated to help distinguish sensitized individuals at minimum or no risk from those at increased risk of developing anaphylaxis include measurement of the ratio of allergen-specific IgE to total IgE, determination of IgE directed at specific allergenic epitopes, measurement of basophil activation markers by using flow cytometry, and assessment of allergen-specific cytokine responses. Algorithms have been developed for risk assessment of individuals with anaphylaxis, along with a research agenda for studies that could lead to an improved ability to confirm the clinical diagnosis of anaphylaxis and to identify allergensensitized individuals who are at increased risk of anaphylaxis. (J Allergy Clin Immunol 2007;120: S2-24.)

- by Andrew Walls
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- Immunology, Mast Cells, Risk assessment, Hymenoptera

iii Dear Colleagues, Wellcome to the International Conference on Enzyme Science and Technology (ICEST2011). The conference aims to bring together experts and those who are interested in enzyme science, enzyme technology and all related fields. It will include invited lectures, oral and poster presentations. The purpose of the conference is to share the recent developments on enzyme science and technology in the fields of basic research and applications. The main topics will be based on but not limited to biocatalysis, bioinformatics and molecular modelling, industrial use of enzymes, enzymes in medicine and diagnosis, metallomics and metalloenzymes, and improvement in experimental methods for enzymatic studies. There will be also a special forum for young scientists allowing round-table discussions with field experts. This meeting, which is supported Centre Juelich will provide an ideal forum for the exchange of information among specialists from academia and industry. It will be held in a stimulating and open scientific atmosphere to foster the development of new collaborations.

- by yasemin isgor
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- Tyrosine Kinase Receptor, Protein Tyrosine Kinase, GSTP1, Glutathione Transferase
- by Alan Trounson
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- Genetics, Animal Studies, Cystic Fibrosis, Apoptosis
- by Maher Albitar
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- Cancer, Tyrosine Kinase Receptor, Bone marrow, Aged

Trastuzumab is a monoclonal antibody targeted against the HER2 tyrosine kinase receptor. The majority of patients with metastatic breast cancer who initially respond to trastuzumab develop resistance within one year of treatment initiation, and in the adjuvant setting 15% of patients still relapse despite trastuzumab-based therapy. In this review, we discuss potential mechanisms of antitumor activity by trastuzumab, and how these mechanisms become altered to promote therapeutic resistance. We also discuss novel therapies that may improve the efficacy of trastuzumab, and that offer hope that the survival of breast cancer patients with HER2-overexpressing tumors can be vastly improved.

Background: The vestibular system provides the primary input of our sense of balance and spatial orientation. Dysfunction of the vestibular system can severely affect a person's quality of life. Therefore, understanding the molecular basis of vestibular neuron survival, maintenance, and innervation of the target sensory epithelia is fundamental.

- by Bernd Fritzsch
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- Animal Behavior, Quality of life, Signal Transduction, Vestibular System

The lens epithelium can be separated into two regions, the nondividing central zone and the equator, the site of all division in the normal lens. In the present study, the distribution of epithelial growth factor (EGF)/epithelial growth factor receptor (EGFR) signaling components was investigated and related to mitotic distribution in the lens. Anterior and equatorial regions of the native epithelium were prepared separately from donor lenses. In vitro capsular bags were prepared from donor eyes and cultured. Receptor distribution was determined by immunocytochemistry and RT-PCR. Western blot analysis of phospholipase C (PLC)-gamma and extracellular signal-regulated kinase (ERK; total and active) was performed on cell lysates. Function was determined by calcium imaging of Fura-2-AM-loaded cells and also, in the case of capsular bags, by cell growth. Immunocytochemistry and RT-PCR showed an even distribution of EGFR across the native epithelium. Whole lenses, however, exhibited only ...

- by Michael Wormstone
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- Calcium, Western blotting, Signal Transduction, Biological Sciences

G protein-coupled receptors (GPCRs) are involved in most physiological processes, many of them being engaged in fully differentiated cells. These receptors couple to transducers of their own, primarily G proteins and β-arrestins, which launch intracellular signalling cascades. Some of these signalling events regulate the translational machinery to fine-tune general cell metabolism or to alter protein expression pattern. Though extensively documented for tyrosine kinase receptors, translational regulation by GPCRs is still poorly appreciated. The objective of this review paper is to address the following questions: i) is there a "GPCR signature" impacting on the translational machinery, and ultimately on the type of mRNA translated? ii) are the regulatory networks involved similar as those utilized by tyrosine kinase receptors? In particular, we will discuss the specific features of translational control mediated by GPCRs and highlight the intrinsic properties of GPCRs these mechanisms could rely on.

- by Eric Reiter and +1
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- Signal Transduction, Cellular Signalling, Cell Differentiation, Par

Preface vii animal production) traditions represent the extremes of this separation. As the end of the century approached, all the infrastructure of a mature network was well-established, under the umbrella of COST, through meetings, workshops, a newsletter, a web-site, mailing-lists, and a searchable database of workers in the field. It seemed a good moment to draw together the varied scientific threads of the network and to join with colleagues worldwide in attempting to define just where we had reached in the field of mammary gland biology and the directions in which we were heading. Thus, although the Tours Conference owed its existence to the COST European network, the contributions of scientists from many countries both inside and outside the EU/COST orbit, ensured that the dimensions of this defining moment were truly international.

- by Volker Brinkmann
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- Morphogenesis, Signal Transduction, Cell Differentiation, Mice
- by Jonas Cicenas
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- Cancer, Breast Cancer, Biomarkers, Cancer Biology
- by Dragan Primorac
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- Gastroenterology, Survival Analysis, Gene expression, Colorectal cancer

I. Đại cương về Nhà nước 1. Nguồn gốc và bản chất Nhà nước 1.1. Tổ chức xã hội và quyền lực trong xã hội cộng sản nguyên thuỷ Từ thời kỳ cổ đại và trung đại đã có nhiều tư tưởng tiếp cận và đưa ra những lý giải khác nhau về nguồn gốc nhà nước. Các nhà tư tưởng theo thuyết thần học cho rằng: Thượng đế là người sắp đặt trật tự xã hội, nhà nước là do thượng đế sáng tạo ra để bảo vệ trật tự chung. Do vậy nhà nước là lực lượng siêu nhân, quyền lực nhà nước là vĩnh cửu và sự phục tùng quyền lực là cần thiết và tất yếu. Trong khi đó, những nhà tư tưởng theo thuyết gia trưởng lại cho rằng nhà nước là kết quả phát triển của gia đình, là hình thức tổ chức tự nhiên của cuộc sống con người.

- by phuong le
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- Genetics, Multidisciplinary, Mutagenesis, Mice

Structural chromosome aberrations are known hallmarks of many solid tumors. In the papillary form of thyroid cancer (PTC), for example, activation of the receptor tyrosine kinase (RTK) genes, ret or the neurotrophic tyrosine kinase receptor type I (NTRK1) by intra-or interchromosomal rearrangements have been suggested as a cause of the disease. The 1986 accident at the nuclear power plant in Chernobyl, Ukraine, led to the uncontrolled release of high levels of radioisotopes. Ten years later, the incidence of childhood papillary thyroid cancer (chPTC) near Chernobyl had risen by two orders of magnitude. Tumors removed from some of these patients showed aberrant expression of the ret RTK gene due to a ret/PTC1 or ret/PTC3 rearrangement involving chromosome 10. However, many cultured chPTC cells show a normal G-banded karyotype and no

- by Ulli Weier
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- Genetics, Flow Cytometry, Gene expression, Thyroid Cancer

The transient receptor potential vanilloid 1 (TRPV1) is an excitatory cation channel, rather selectively expressed in a subpopulation of nociceptive, primary sensory neurons that promote neurogenic inflammation via neuropeptide release. TRPV1 is activated by noxious temperature, low extracellular pH and diverse lipid derivatives, and is uniquely sensitive to vanilloid molecules, including capsaicin. TRPV1 expression and sensitivity is highly regulated by diverse G protein-coupled and tyrosine kinase receptors. Other exogenous or endogenous chemical agents, including reactive oxygen species, ethanol and hydrogen sulphide sensitize/activate TRPV1. In the airways, TRPV1 agonists cause cough, bronchoconstriction, microvascular leakage, hyperreactivity and hypersecretion. Patients with asthma and chronic obstructive pulmonary disease are more sensitive to the tussive effect of TRPV1 agonists and TRPV1 activation may contribute to respiratory symptoms caused by acidic media present in the airways during asthma exacerbation, gastroesophageal reflux induced asthma or in other conditions. TRPV1 antagonists may be useful in the treatment of these diseases.

- by Serena Materazzi
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- Asthma, Tyrosine Kinase Receptor, Sensory Neuron, Neurons

Liposomes and Flt3 ligand (Flt3L), a ligand for the fms-like tyrosine kinase receptor Flt3/ FLK2, can augment the immune response to an HIV peptide vaccine. The HGP-30 peptide used in these studies is a synthetic peptide that corresponds to a highly conserved region of HIV-1 p17 gag (amino acids 86-115). Mice were immunized with HGP-30 or HGP-30 conjugated to keyhole limpet hemocyanin (KLH) and delayed-type hypersensitivity (DTH) responses, antibody (IgG) amount and antigen-specific proliferative responses by spleen cells were used to monitor the immune response. Daily injections of Flt3L prior to HGP-30 administration enhanced significantly an antigen-specific lymphocyte proliferation response when compared with Flt3L, HGP-30 alone or HGP-30 containing liposomes. Intravenous administration of HGP-30 was superior to intramuscular (i.m.) immunization for the induction of DTH responses. The HGP-30/KLH containing liposomes enhanced both DTH and antibody responses, while liposomes conta...

- by Prahlad Parajuli
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- Immune response, Membrane Proteins, Immunopharmacology, Dendritic Cells

To understand how extracellular signals may produce long-term effects in neural cells, we have analyzed the mechanism by which neurotransmitters and growth factors induce phosphorylation of the transcription factor cAMP response element binding protein (CREB) in cortical oligodendrocyte progenitor (OP) cells. Activation of glutamate receptor channels by kainate, as well as stimulation of G-protein-coupled cholinergic receptors by carbachol and tyrosine kinase receptors by basic fibroblast growth factor (bFGF), rapidly leads to mitogen-activated protein kinase (MAPK) phosphorylation and ribosomal S6 kinase (RSK) activation. Kainate and carbachol activation of the MAPK pathway requires extracellular calcium influx and is accompanied by protein kinase C (PKC) induction, with no significant increase in GTP binding to Ras. Conversely, growth factor-stimulated MAPK phosphorylation is independent of extracellular calcium and is accompanied by Ras activation. Both basal and stimulated MAPK ...

- by John Blenis
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- Stem Cells, Kinetics, Calcium, Signal Transduction

-Protein tyrosine phosphorylation induced by arachidonic acid (AA), an important lipid second messenger, was investigated in rabbit renal proximal tubule epithelial cells. AA stimulated tyrosine phosphorylation of a number of proteins with estimated molecular weights of 42, 44, 52, 56, 85, and 170/180 kDa. The phosphoproteins pp44 and pp42 were identified as 2 isoforms of mitogen-activated protein kinase (MAPK). Phosphorylation of MAPK in response to AA was transient, dose-dependent, and accompanied by an increase in its activity. The mechanism of AA-induced MAPK activation in RTE cells was protein kinase C-independent and involved tyrosine phosphorylation of adaptor protein Shc and its association with Grb2-Sos complex. Moreover, stimulation of RTE cells with AA resulted in significant phosphorylation of epidermal growth factor (EGF) receptor and its association with Shc. The effect of AA on EGF receptor phosphorylation, its association with Shc, and MAPK activation was similar to the effect of 1 ng/mL EGF. Tyrphostin AG1478, a specific inhibitor of EGF receptor tyrosine kinase activity, completely blocked the effects of AA and EGF but not phorbol ester on MAPK phosphorylation. These data suggest that in renal tubular epithelial cells, the mechanism of AA-induced MAPK activation involves tyrosine phosphorylation of EGF receptor and its association with Shc and Grb2-Sos complex. Given the critical role of AA in signaling linked to G protein-coupled receptors (GPCRs), these observations provide a mechanism for cross talk between GPCRs linked to phospholipases and the tyrosine kinase receptor signaling cascades.

- by Janice Douglas
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- Membrane Proteins, Hypertension, Tyrosine Kinase Receptor, Phosphorylation

EphA2 (Eck) is a tyrosine kinase receptor that is overexpressed in several human cancers such as breast, colon, lung, prostate, gastric carcinoma, and metastatic melanoma but not in nonmalignant counterparts. To validate EphA2 as a tumor antigen recognized by CD8+ T lymphocytes, we used reverse immunology approach to identify HLA-A*0201-restricted epitopes. Peptides bearing the HLA-A*0201-specific anchor motifs were analyzed for their capacity to bind and stabilize the HLA-A*0201 molecules. Two peptides, EphA2(58) and EphA2(550), with a high affinity for HLA-A*0201 were selected. Both peptides were immunogenic in the HLA-A*0201-transgenic HHD mice. Interestingly, peptide-specific murine CTLs cell lines responded to COS-7 cells coexpressing HLA-A*0201 and EphA2 and to EphA2-positive human tumor cells of various origin (renal cell, lung, and colon carcinoma and sarcoma). This demonstrates that EphA2(58) and EphA2(550) are naturally processed from endogenous EphA2. In addition, EphA2(5...

- by Stephanie Graff-dubois
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- Cancer, Prostate Cancer, Cercopithecus aethiops, Cell line

The paradigm of cell surface proteoglycan function has been centered on the role of the ectoplasmic heparan sulfate (HS) chains as acceptors of a wide array of ligands, including extracellular matrix (ECM) proteins and soluble growth factors. Within this picture, the core proteins were assigned only a passive role of carrying the glycosaminoglycan (GAG) chains without direct participation in mediating outside-in signals generated by the binding of the above ligands. It appears now, however, that, side by side with the integrins and the tyrosine kinase receptors, the core proteins of the syndecan family of transmembrane proteoglycans are involved in signaling. The highly conserved tails of all the four members of the syndecan family contain a carboxy-terminal PDZ (Postsynaptic density 95, Disk large, Zona occludens-1)-binding motif, capable of forming multimolecular complexes through the binding of PDZ adaptor proteins. The cytoplasmic tail of the ubiquitously expressed syndecan-4 is distinct from the other syndecans in its capacity to bind phosphatidylinositol 4,5-bisphosphate (PIP2) and to activate protein kinase C (PKC) alpha. These properties may confer on syndecan-4 specific and unique signaling functions.

- by Jean Crabtree
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- Microbiology, Medical Microbiology, Helicobacter pylori, Cell Division

Head and neck squamous cell carcinomas (HNSCC) are characterized by a marked propensity for local invasion and spread to cervical lymph nodes, with distant metastases developing in 30-40% of cases. HPV-16 is an important risk factor for HNSCC. How HPV enhances susceptibility to HNSCC is not fully understood, but seems to involve cofactors. In this study, we examined the effect of the cooperation between HPV-16 and the tyrosine kinase receptor ErbB-2 on E-cadherin/catenin complex patterns and neoplastic transformation of human normal oral epithelial (NOE) cells. We report that overexpression of ErbB-2 or E6/E7 alone does not affect E-cadherin/catenin complex patterns nor does it induce cell transformation of NOE cells. In contrast, coexpression of E6/E7 and ErbB-2 downregulates E-cadherin and catenin expression. This is accompanied by cytoplasmic localization of E-cadherin, as well as nuclear translocation of a, b, and c-catenins. Furthermore, we demonstrate that E6/E7 cooperate with overexpressed ErbB-2 to induce tumor formation in nude mice and to upregulate cyclin D1 and c-myc expression. Our data suggest that E6/E7 cooperate with ErbB-2 in head and neck carcinogenesis, at least in part, via the conversion of b-catenin from a cell adhesion to a nuclear function, that is, to act as a potential transcriptional regulator. This conversion leads to the upregulation of cyclin D1, c-myc and other oncoproteins necessary for alteration of the E-cadherin/catenin complex and cell transformation of NOE cells.

- by Lily Yen and +1
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- Transformation, Cell Adhesion, Transcription Regulation, Western blotting

The tyrosine kinase receptor KIT plays a major role in gastrointestinal stromal tumors (GISTs) oncogenesis. Indeed, 95% of GISTs express KIT protein, and about 70% exhibit activating mutations of the KIT gene. However, little is known about KIT overexpression mechanisms in these tumors, and the correlation with KIT mutations. GISTs with mutations within exon 11 (n = 12) or 9 (n = 1) of KIT were compared with GISTs without KIT mutations in exons 9, 11, 13, and 17 (n = 10), two of them had PDGFRA mutations. KIT amplification was studied by real-time PCR of KIT and beta-ACTIN genes, and by fluorescence in situ hybridization (FISH) using KIT and chromosome 4 centromere specific probes. KIT transcripts and protein expression were quantified by reverse transcription real-time PCR and Western blot respectively. Genomic analysis revealed a single mutated GIST with KIT amplification. KIT protein and RNA levels were highly variable in GISTs but closely correlated (r = 0.82, P < 1.10 À5 ), and were higher in GISTs with KIT mutations ( P = 0.07 and P = 0.03 respectively). In conclusion, contrasting with the regulation of other tyrosine kinase receptors, KIT overexpression in GISTs is rarely related to a gene amplification, which suggests a deregulation of KIT gene transcription. D

- by Maria Debiec-Rychter
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- Gene expression, Biological Sciences, real time PCR, Mutation

Sorbonne Université (Pierre & Marie Curie, Paris VI), Faculty of Sciences. N° national de thèse: 2006PA066115 https://www.worldcat.org/search?q=no%3A494198160 During development of the nervous system, Receptors with Tyrosine Kinase (RTK) activity play essential roles in a wide variety of fundamental physiological cellular processes such as proliferation, survival, or differentiation. In the RTK family, Alk has been one of the last to be identified. It remains, to date, considered as orphan, as no ligand has been yet attributed in vertebrates. It is essentially expressed in specific regions of the central and peripheral nervous system, and transiently during development. This expression strongly suggests therefore that it could play a fundamental role in the development and functioning of the nervous system. This role still remains however to be clearly identified. Thus, the studies I conducted these last years participate to the general understanding of the role of ALK in neuronal development. My thesis works focused therefore on the study of its function and mechanisms of action, in the frame of the neuronal differentiation of PC12 cells. These works also attempted, more generally, to bring matter to the current thoughts concerning the biochemical/cellular factors and parameters that can determine the specificity of biological responses and their cellular mechanisms of action. Specifically, they focused on the study of the role of the subcellular localization of a Tyrosine Kinase domain (of ALK, in particular) in the orchestration of the signals that determine neuronal development. Therefore, the results I obtained during this thesis, in their whole, have allowed not only to better understand the signalling pathways and the biological effects induced by the activation of the receptor ALK, but they further strongly support that membrane attachment of the ALK Tyrosine Kinase domain is crucial for the control and specificity of the signalling and biological pathways engaged by ALK. Thus, these works, more generally, underline the fundamental importance of the subcellular localization of a Tyrosine Kinase domain in the decision of the fate in which the cell will be engaged, and in particular the immature neuronal cell during the development of the nervous system.

- by Jean Y. Gouzi
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- Neuroscience, Tyrosine Kinase Receptor, Cell Signalling, Neuronal Differentiation
- by Helen Michael
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- Histology, Immunohistochemistry, Clinical Biochemistry, Adolescent

The expression of neurotrophins and neurotrophin receptors in non-neural tissue is related to tissue remodeling, differentiation, proliferation and migration of target cells. The literature yields contradictory results on neurotrophin and neurotrophin receptor expression in the liver. We show immunoreactivity to antibodies to nerve growth factor (NGF), brain-derived neurotrophin (BDNF), neurotrophin 3 (NT-3), neurotrophin 4/5 (NT-4/5), the low-affinity nerve growth factor receptor p75 and the high-affinity tyrosine kinase receptors (Trk) B and C in hepatic stellate cells and weak reactivity for BDNF, NT-3, and NT-4/5 in hepatocytes, in cryosections of human and rat liver, in normal and varying pathologic conditions. Immunoreactivity is unequivocally localized to hepatic stellate cells by double staining with ␣-smooth muscle actin (␣-SMA) and desmin, studied by confocal laser scanning microscopy. Finally, the presence of mRNA transcripts for the different neurotrophins and neurotrophin receptors, with the exception of Trk-B, is shown by reverse transcription polymerase chain reaction (RT-PCR) on RNA extracted from freshly isolated rat hepatic stellate cells, compared with hepatocyte RNA. Hepatocyte RNA was found to contain BDNF, NT-3, NT-4/5 mRNA (which is compatible with the immunohistochemical findings) and Trk-A mRNA. In conclusion, hepatic stellate cells are a source of several neurotrophins in the liver and they express neurotrophin receptors. These findings correspond with the known involvement of hepatic stellate cells in tissue remodeling, their production of extracellular matrix components and their proliferation in acute necrotizing liver pathology. In analogy with findings in other organs and systems, neurotrophins are hypothesized to play a role in the pathophysiology of liver disease. (HEPATOLOGY 2001;33: 148-158.)

- by Carl Denef
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- Immunohistochemistry, Fluorescent Dyes and Reagents, Extracellular Matrix, Hepatology

During visual system development, interactions between Eph tyrosine kinase receptors and their ligands, the ephrins, guide retinal ganglion cell (RGC) axons to their topographic targets in the optic tectum. Here we show that Eph/ephrin interactions are also involved in restoring topography during RGC axon regeneration in goldfish. Following optic nerve crush, EphA/ephrin-A interactions were blocked by intracranial injections of recombinant Eph receptor (EphA3-AP) or phosphoinositol phospholipase-C. Topographic errors with multiple inputs to some tectal loci were detected electrophysiologically and increased projections to caudal tectum demonstrated by RT-97 immunohistochemistry. In EphA3-AP-injected fish, ephrin-A2-expressing cells in the retino-recipient tectal layers were reduced in number compared to controls and their distribution was no longer graded. The findings, supported by in vitro studies, implicate EphA/ephrin-A interactions in restoring precise topography and in regulating ephrin-A2 expression during regeneration. D

- by Caroline Brennan
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- Cognitive Science, Immunohistochemistry, Optic Nerve, Tyrosine Kinase Receptor

The interactions between dendritic cells (DCs) and T cells determine the fate of an immune response to pathogenic microbes and to harmless allergens alike. The interactions between DCs and T cells is dependent on the maturation and differentiation status of DCs. This status is affected by the cellular lineage of the DCs and by signals that the cells receive from the environment and from T cells. A specific subpopulation of DCs (dendritic cell type 2 [DC2]) induces the development of T helper 2 (Th2) responses. Unregulated Th2 responses induce and cause inflammation in allergy and asthma. If it would be possible to target DC2 cells for prophylactic or therapeutic measures, then it may be possible to change the T cell response to allergens on a long-term basis. In the past few years, there have been major research efforts to elucidate molecular determinants of DC maturation. This review summarizes the new findings and their potential for future clinical application.

- by A. Banz
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- Immune response, Cytokines, Dendritic Cells, Toll Like Receptors

Previous work has shown that brain-derived neurotrophic factor (BDNF) and its receptor, tyrosine kinase receptor B (TrkB), are involved in appetitive behavior. Here we show that BDNF in the ventral tegmental area-nucleus accumbens... more

- by carlos bolaños
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- Animal Behavior, Depression, Immunohistochemistry, Swimming

BACKGROUND: Human epidermal growth factor receptor (HER) downstream signaling kinases have important effects on tumor response to anti-HER monoclonal antibodies and tyrosine kinase inhibitors. We validated an assay that uses... more

- by Thierry Bastogne
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- Breast Cancer, Immunohistochemistry, Western blotting, Signal Transduction

c-kit (CD117) is a tyrosine kinase receptor involved in the proliferation, differentiation, and secretory functions of various cells. In experimental animal models, ckit has been detected in the pars intermedia of the normal pituitary gland and in α-melanocyte-stimulating-hormonepositive adenomas and it has been suggested that it plays a role in regulating adrenocorticotropic hormone (ACTH) secretion. To the best of our knowledge, the expression of c-kit in normal human pituitary cells and in pituitary adenomas has never been reported, so the possible biological role of this receptor in the control of pituitary hormone secretion remains unclear. The aim of this study was to evaluate the immunohistochemical expression of c-kit in normal human pituitary glands and in a series of 62 wellcharacterized pituitary adenomas. In normal adenohypophyses, several cells, mainly located in the central mucoid wedge, showed a c-kit immunoreactivity (IR). Double label immunostaining procedures showed that the c-kit-IR cells corresponded to ACTH cells. Out of 62 adenomas, 15 (24%) were c-kit-IR, including 7/16 (44%) ACTH cell, 3/7 (42%) null cell, 4/11 (36%) α-subunit cell, and 1/11 (10%) folliclestimulating hormone-luteinizing hormone cell adenomas. By contrast, all ten prolactin cell and seven growth hormone cell adenomas were c-kit negative. These data suggest that, in normal conditions, c-kit may be involved in the pituitaryadrenal axis regulation.

- by Carlo Capella and +1
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- Immunohistochemistry, Adolescent, Western blotting, Growth Hormone

Background: Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive genetic disease characterized by the lack of reaction to noxious stimuli and anhidrosis. It is caused by mutations in the NTRK1 gene, which encodes the high affinity tyrosine kinase receptor I for Neurotrophic Growth Factor (NGF). Case Presentation: We present the case of a female patient diagnosed with CIPA at the age of 8 months. The patient is currently 6 years old and her psychomotor development conforms to her age (RMN, SPECT and psychological study are in the range of normality). PCR amplification of DNA, followed by direct sequencing, was used to investigate the presence of NTRK1 gene mutations. Reverse transcriptase (RT)-PCR amplification of RNA, followed by cloning and sequencing of isolated RT-PCR products was used to characterize the effect of the mutations on NTRK1 mRNA splicing. The clinical diagnosis of CIPA was confirmed by the detection of two splicesite mutations in NTRK1, revealing that the patient was a compound heterozygote at this gene. One of these alterations, c.574+1G>A, is located at the splice donor site of intron 5. We also found a second mutation, c.2206-2 A>G, not previously reported in the literature, which is located at the splice acceptor site of intron 16. Each parent was confirmed to be a carrier for one of the mutations by DNA sequencing analysis. It has been proposed that the c.574+1G>A mutation would cause exon 5 skipping during NTRK1 mRNA splicing. We could confirm this prediction and, more importantly, we provide evidence that the novel c.2206-2A>G mutation also disrupts normal NTRK1 splicing, leading to the use of an alternative splice acceptor site within exon 17. As a consequence, this mutation would result in the production of a mutant NTRK1 protein with a seven aminoacid in-frame deletion in its tyrosine kinase domain. Conclusions: We present the first description of a CIPA-associated NTRK1 mutation causing a short interstitial deletion in the tyrosine kinase domain of the receptor. The possible phenotypical implications of this mutation are discussed.

- by Jose Rodriguez
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- Genetics, Child, Tyrosine Kinase Receptor, Pain Perception
- by Lily Yen
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- Cell Division, Lung Cancer, Cell line, Tyrosine Kinase Receptor

We herein disclose a novel chemical series of benzimidazole-ureas as inhibitors of VEGFR-2 and TIE-2 kinase receptors, both of which are implicated in angiogenesis. Structure-activity relationship (SAR) studies elucidated a critical role for the N1 nitrogen of both the benzimidazole (segment E) and urea (segment B) moieties. The SAR results were also supported by the X-ray crystallographic elucidation of the role of the N1 nitrogen and the urea moiety when the benzimidazole-urea compounds were bound to the VEGFR-2 enzyme. The left side phenyl ring (segment A) occupies the backpocket where a 3-hydrophobic substituent was favored for TIE-2 activity.

Cancer is a genetic disease and this concept is now widely exploited by both scientists and clinicians to design new targeted molecules. Indeed many data have already allowed us to ameliorate not only our knowledge about cancer onset, but also about patients treatment. Correlation between mutations in cancer alleles and drug response is a key point to identify drugs that match the genetic profile of each individual tumors. On the other hand, experience derived from inhibition of tyrosine kinase receptors has pointed out that targeted treatment is really successful only in a small subset of tumors. The latter are eventually addicted to those genetic alterations which are responsible for receptors activation and for the continued expression of their signalling. Overall these observations provide a strong rationale for a molecular-based diagnosis and patients selection for targeted therapies. This review analyses the current state of the art of molecularly-tailored pharmacological approach to lung cancer, one of the biggest killers among human solid tumors. Main relevance is addressed to genetic lesions activating the EGFR pathway transducers, focusing on their role as markers of targeted drug response.

- by Roberta Scabini
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- Genetics, Respiratory Medicine, Signal Transduction, Lung Cancer
- by Joan Comella
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- Cognitive Science, Molecular Evolution, Signal Transduction, Phylogeny

Cell-cell interaction is important in the expansion of leukemic cells and of solid tumors. Steel factor (SF) or Kit ligand is produced as a membrane-bound form (mSF) and a soluble form. Because both primary gynecological tumors and primary leukemic cells from patients with acute myeloblastic leukemia (AML) have been shown to coexpress c-Kit and SF, we addressed the question of whether mSF could contribute to cell interaction in these cancers. Investigations on primary cervical carcinomas have been hindered by the fact that the cells do not grow in culture. We report herein the establishment of two cervical carcinoma cell lines, CALO and INBL, that reproduce the pattern of SF/c-Kit expression observed in primary tumor samples. In addition, these cells exhibit marked density-dependent growth much in the same way as AML blasts. Using an antisense strategy with phosphorothioate-modified oligonucleotides that specifically target SF without affecting other surface markers, we provide dire...

- by BENNY WEISS and +1
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- Cancer, Cell Division, Cercopithecus aethiops, Cell line

Expression of the epidermal growth factor (EGF) and activation of its receptor (EGFR), a tyrosine kinase, are associated with progressive growth of head and neck cancer. Expression of the vascular endothelial growth factor (VEGF) is associated with angiogenesis and progressive growth of tumor. The tyrosine kinase inhibitor NVP-AEE788 (AEE788) blocks the EGF and VEGF signaling pathways. We examined the effects of AEE788 administered alone, or with paclitaxel (Taxol), on the progression of human head and neck cancer implanted orthotopically into nude mice. Cells of two different human oral cancer lines, JMAR and MDA1986, were injected into the tongues of nude mice. Mice with established tumors were randomized to receive three times per week oral AEE788, once weekly injected paclitaxel, AEE788 plus paclitaxel, or placebo. Oral tumors were resected at necropsy. Kinase activity, cell proliferation, apoptosis, and mean vessel density were determined by immunohistochemical immunofluorescent staining. AEE788 inhibited cell growth, induced apoptosis, and reduced the phosphorylation of EGFR, VEGFR-2, AKT, and mitogen-activated protein kinase in both cell lines. Mice treated with AEE788 and AEE788 plus paclitaxel had decreased microvessel density, decreased proliferative index, and increased apoptosis. Hence, AEE788 inhibited tumor vascularization and growth and prolonged survival. Inhibition of EGFR and VEGFR phosphorylation by AEE788 effectively inhibits cellular proliferation of squamous cell carcinoma of the head and neck, induces apoptosis of tumor endothelial cells and tumor cells, and is well tolerated in mice. These data recommend the consideration of patients with head and neck cancer for inclusion in clinical trials of AEE788.

- by Dao Doan
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- Clinical Trial, Cancer, Immunohistochemistry, Signal Transduction

We evaluated the role of acetyl-l-carnitine (ALCAR) in protecting primary motoneuron cultures exposed to excitotoxic agents or serum-brain derived neurotrophic factor (BDNF) deprived. To exclude that ALCAR works as a metabolic source, we compared its effects with those of l-carnitine (L-CAR), that seems to have no neurotrophic effect. A concentration of 10 mM ALCAR, but not L-CAR, significantly reduced the toxic effect of 50 mM N-methyl-d-aspartate (NMDA, % viability: NMDA 45.4^2.80, NMDA 1 ALCAR 90.8^11.8; P , 0:01) and of 5 mM kainate in cultured motoneurons (% viability: kainate 40.66^10.73; kainate 1 ALCAR 63.80^13.88; P , 0:05). The effect was due to a shift to the right of the doseresponse curve for kainate (EC50 for kainate 5.99^1.012 mM; kainate 1 ALCAR 8.62^1.13 mM; P , 0:05). ALCAR, but not L-CAR, significantly protected against BDNF and serum-deprivation reducing the apoptotic cell death (% viability respect to control: without BDNF/serum 61.8^13.3: without BDNF/serum 1 ALCAR 111.8^13.9; P , 0:01). Immunocytochemistry showed an increase in choline acethyltransferase and tyrosine kinaseB receptors in motoneurons treated with ALCAR but not with L-CAR. These results suggest that ALCAR treatment improves the motoneurons activity, acting as a neurotrophic factor. q

Growth factor receptors and their ligands not only regulate normal cell processes but have been also identified as key regulators of human cancer formation. The epidermal growth factor receptor (EGFR/ErbB1/HER1) belongs to the ErbB/HER-family of tyrosine kinase receptors (RTKs). These trans-membrane proteins are activated following binding with peptide growth factors of the EGFfamily of proteins. Several evidences suggest that cooperation of multiple ErbB receptors and ligands is required for the induction of cell transformation. In this respect, EGFR, upon activation, sustains a complex and redundant network of signal transduction pathways with the contribution of other trans-membrane receptors. EGFR has been found to be expressed and altered in a variety of malignancies and clearly it plays a significant role in tumor development and progression, including cell proliferation, regulation of apoptotic cell death, angiogenesis and metastatic spread. Moreover, amplification of the EGFR gene and mutations in the EGFR tyrosine kinase domain have been recently reported in human carcinomas. As a result, investigators have developed approaches to inhibit the effects of EGFR activation, with the aim of blocking tumor growth and invasion. A number of agents targeting EGFR, including specific antibodies directed against its ligand-binding domain and small molecules inhibiting its tyrosine kinase activity are either in clinical trials or are already approved for clinical treatment.

- by Roberto Bianco
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- Clinical Trial, Cancer treatment, Signal Transduction, Mutation

During development, Met signaling regulates a range of cellular processes including growth, differentiation, survival and migration. The Met gene encodes a tyrosine kinase receptor, which is activated by Hgf (hepatocyte growth factor) ligand. Altered regulation of human MET expression has been implicated in autism. In mouse, Met signaling has been shown to regulate cerebellum development. Since abnormalities in cerebellar structure have been reported in some autistic patients, we have used the zebrafish to address the role of Met signaling during cerebellar development and thus further our understanding of the molecular basis of autism. We find that zebrafish met is expressed in the cerebellar primordium, later localizing to the ventricular zone (VZ), with the hgf1 and hgf2 ligand genes expressed in surrounding tissues. Morpholino knockdown of either Met or its Hgf ligands leads to a significant reduction in the size of the cerebellum, primarily as a consequence of reduced proliferation. Met signaling knockdown disrupts specification of VZderived cell types, and also reduces granule cell numbers, due to an early effect on cerebellar proliferation and/or as an indirect consequence of loss of signals from VZ-derived cells later in development. These patterning defects preclude analysis of cerebellar neuronal migration, but we have found that Met signaling is necessary for migration of hindbrain facial motor neurons. In summary, we have described roles for Met signaling in coordinating growth and cell type specification within the developing cerebellum, and in migration of hindbrain neurons. These functions may underlie the correlation between altered MET regulation and autism spectrum disorders.

- by Robert Ho and +1
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- Developmental Biology, Motor neuron, Gene expression, Signal Transduction

Gangliosides have long been implicated in cell growth regulation and play an important role as modulators in protein phosphorylation. In order to better understand how glycosphingolipids and growth factors interact, we examined the modulation of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) effects on retinal Müller glial cells (RMG), following modification of their GG composition. Treatment of MG cells with GG (GM1, GT1b) and asialoGM1 resulted in modifications of several aspects of cellular responses to EGF- and FGF-receptor (R) activation: mitogenesis, cell migration, tyrosine phosphorylation of the EGF-R and FGF-R and even their cellular substrates were particularly influenced by GG. Indeed GG caused modifications of EGF-R and FGF-R autophosphorylation kinetics. GG long term effects (mitogenesis and migration) correlate with short term effects (tyrosine phosphorylation) and differences in receptor tyrosine kinase signalling could explain the specificity...

- by Emmanuelle Meuillet
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- Kinetics, Cell Migration, Signal Transduction, Tyrosine Kinase Receptor

G protein-coupled receptors (GPCRs) are seven transmembrane-spanning proteins belonging to a large family of cell-surface receptors involved in many intracellular signaling cascades. Despite GPCRs lack intrinsic tyrosine kinase activity, tyrosine phosphorylation of a tyrosine kinase receptor (RTK) occurs in response to binding of specific agonists of several such receptors, triggering intracellular mitogenic cascades. This suggests that the notion that GPCRs are associated with the regulation of post-mitotic cell functions is no longer believable. Crosstalk between GPCR and RTK may occur by different molecular mechanism such as the activation of metalloproteases, which can induce the metalloprotease-dependent release of RTK ligands, or in a ligand-independent manner involving membrane associated non-receptor tyrosine kinases, such as c-Src. Reactive oxygen species (ROS) are also implicated as signaling OPEN ACCESS the activation of protein kinase C (PKC) isoforms. PKCα mediates feedback inhibition of RTK transactivation during GPCR stimulation. Recent data have expanded the coverage of transactivation to include Serine/Threonine kinase receptors and Toll-like receptors. Herein, we discuss the main mechanisms of GPCR-mediated cell-surface receptors transactivation and the pathways involved in intracellular responses induced by GPCR agonists. These studies may suggest the design of novel strategies for therapeutic interventions.

- by efkan duraklı
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- Bioengineering, Pharmacology, Biochemistry, Pharmacy