Eph signalling functions downstream of Val to regulate cell sorting and boundary formation in the caudal hindbrain

Development ◽  
2001 ◽  
Vol 128 (4) ◽  
pp. 571-580 ◽  
Author(s):  
J. Cooke ◽  
C. Moens ◽  
L. Roth ◽  
L. Durbin ◽  
K. Shiomi ◽  
...  
Keyword(s):  
Cell Sorting ◽  
Tyrosine Kinases ◽  
Bzip Transcription Factor ◽  
Boundary Formation ◽  
Spatial Regulation ◽  
Genetic Mosaic ◽  
Mosaic Approach ◽  
Mediate Cell ◽  
Neural Crest Migration ◽  
Mutant Cells

Rhombomeres are segmental units of the developing vertebrate hindbrain that underlie the reiterated organisation of cranial neural crest migration and neuronal differentiation. valentino (val), a zebrafish homologue of the mouse bzip transcription factor-encoding gene, kreisler, is required for segment boundary formation caudal to rhombomere 4 (r4). val is normally expressed in r5/6 and is required for cells to contribute to this region. In val(−) mutants, rX, a region one rhombomere in length and of mixed identity, lies between r4 and r7. While a number of genes involved in establishing rhombomeric identity are known, it is still largely unclear how segmental integrity is established and boundaries are formed. Members of the Eph family of receptor tyrosine kinases and their ligands, the ephrins, are candidates for functioning in rhombomere boundary formation. Indeed, expression of the receptor ephB4a coincides with val in r5/6, whilst ephrin-B2a, which encodes a ligand for EphB4a, is expressed in r4 and r7, complementary to the domain of val expression. Here we show that in val(−) embryos, ephB4a expression is downregulated and ephrin-B2a expression is upregulated between r4 and r7, indicating that Val is normally required to establish the mutually exclusive expression domains of these two genes. We show that juxtaposition of ephB4a-expressing cells and ephrin-B2a-expressing cells in the hindbrain leads to boundary formation. Loss of the normal spatial regulation of eph/ephrin expression in val mutants correlates not only with absence of boundaries but also with the inability of mutant cells to contribute to wild-type r5/6. Using a genetic mosaic approach, we show that spatially inappropriate Eph signalling underlies the repulsion of val(−) cells from r5/6. We propose that Val controls eph expression and that interactions between EphB4a and Ephrin-B2a mediate cell sorting and boundary formation in the segmenting caudal hindbrain.

scholarly journals Spatial regulation of signaling by the coordinated action of the protein tyrosine kinases MET and FER

2018 ◽  
Vol 50 ◽  
pp. 100-110 ◽  
Author(s):  
Jiali Zhang ◽  
Zuo Wang ◽  
Siwei Zhang ◽  
Yanxun Chen ◽  
Xuexue Xiong ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Protein Tyrosine Kinases ◽  
Protein Tyrosine ◽  
Spatial Regulation ◽  
Coordinated Action

scholarly journals Antibody Targeting of Eph Receptors in Cancer

2020 ◽  
Vol 13 (5) ◽  
pp. 88
Author(s):  
Peter W. Janes ◽  
Mary E. Vail ◽  
Hui K. Gan ◽  
Andrew M. Scott
Keyword(s):  
Tumor Microenvironment ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Cell Communication ◽  
Eph Receptors ◽  
Preclinical Models ◽  
Anti Cancer ◽  
Tumor Specificity ◽  
Mediate Cell ◽  
Cancer Activity

The Eph subfamily of receptor tyrosine kinases mediate cell-cell communication controlling cell and tissue patterning during development. While generally less active in adult tissues, they often re-emerge in cancers, particularly on undifferentiated or progenitor cells in tumors and the tumor microenvironment, associated with tumor initiation, angiogenesis and metastasis. Eph receptors are thus attractive therapeutic targets, and monoclonal antibodies have been commonly developed and tested for anti-cancer activity in preclinical models, and in some cases in the clinic. This review summarizes 20 years of research on various antibody-based approaches to target Eph receptors in tumors and the tumor microenvironment, including their mode of action, tumor specificity, and efficacy in pre-clinical and clinical testing.

Identification of Critical Phosporylation Sites within NPM-ALK That Regulate JUNB mRNA Translation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3571-3571
Author(s):  
Claudia Fuchs ◽  
Paul Vesely ◽  
Isabella Bambach ◽  
Silvia Schauer ◽  
Werner Linkesch ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Translational Regulation ◽  
Chromosomal Translocation ◽  
Mrna Translation ◽  
Large Cell ◽  
Wild Type ◽  
Tyrosine Residues ◽  
Anaplastic Lymphoma ◽  
Rps6 Phosphorylation ◽  
Mutant Cells

Abstract Anaplastic large cell lymphoma (ALCL) accounts for approximately 30% of childhood lymphomas and 3% of adult non-Hodgkin lymphomas. The nucleophosmin - anaplastic lymphoma kinase (NPM-ALK) fusion which is the product of a t(2;5)(p23;q35) chromosomal translocation is present in about half of nodal ALCL. Expression of this fusion kinase results in induction of the AP-1 transcription factor JunB and IL-3 independent outgrow of murine hematopoietic Ba/F3 cells. We demonstrated that wild type NPM-ALK increases the amount of ribosomes bound to JUNB mRNA resulting in its more effective translation in large polysomes. The NPM-ALK fusion tyrosine kinase has 20 potential tyrosine residues available for autophosphorylation and phosphorylation by other protein tyrosine kinases. Here we used series of Y-to-F-substituted mutants of NPM-ALK to identify tyrosine residues that are required to regulate the segregation of JUNB mRNAs between polysomes and monosomes as well as ribonucleic particles (RNPs). Neither JUNB transcription nor JunB translation was altered in Ba/F3 cells expressing NPM-ALK mutants Y17F/Y29F/Y67F Y138F/Y152F Y156F/Y191F/Y299F Y378F/Y418F/Y445F and Y646F/Y664F compared to NPM-ALK wild type. Conversely, in NPM-ALK Y567F/Y461F/Y644F mutant cells proliferation was markedly decreased. These cells demonstrated active MEK-ERK pathway, while AKT, mTOR, and rpS6 phosphorylation was impaired. Moreover a shift of JUNB mRNA from the polysomic to the monosomic/mRNP fraction could be observed. In conclusion, we identified specific NPM-ALK phosphorylation sites required to mediate the effect of NPM-ALK on the JUNB translational regulation and therefore provide further insights in the transforming mechanisms of the oncoprotein NPM-ALK.

scholarly journals Fgf/MAPK signalling is a crucial positional cue in somite boundary formation

Development ◽  
2001 ◽  
Vol 128 (23) ◽  
pp. 4873-4880 ◽  
Author(s):  
Atsushi Sawada ◽  
Minori Shinya ◽  
Yun-Jin Jiang ◽  
Atsushi Kawakami ◽  
Atsushi Kuroiwa ◽  
...  
Keyword(s):  
Experimental Manipulation ◽  
Notch Signalling ◽  
Presomitic Mesoderm ◽  
Mapk Activation ◽  
Boundary Formation ◽  
Molecular Oscillator ◽  
Spatial Regulation ◽  
Mapk Signalling ◽  
Temporal And Spatial ◽  
Segmentation Point

The temporal and spatial regulation of somitogenesis requires a molecular oscillator, the segmentation clock. Through Notch signalling, the oscillation in cells is coordinated and translated into a cyclic wave of expression of hairy-related and other genes. The wave sweeps caudorostrally through the presomitic mesoderm (PSM) and finally arrests at the future segmentation point in the anterior PSM. By experimental manipulation and analyses in zebrafish somitogenesis mutants, we have found a novel component involved in this process. We report that the level of Fgf/MAPK activation (highest in the posterior PSM) serves as a positional cue within the PSM that regulates progression of the cyclic wave and thereby governs the positions of somite boundary formation.

Targeting of host cell receptor tyrosine kinases by intracellular pathogens

2019 ◽  
Vol 12 (599) ◽  
pp. eaau9894 ◽  
Author(s):  
Gholamreza Haqshenas ◽  
Christian Doerig
Keyword(s):  
Host Cell ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Cell Receptor ◽  
Host Cells ◽  
Target Cells ◽  
Intracellular Pathogens ◽  
Host Cell Receptor ◽  
Host Signaling ◽  
Mediate Cell

Intracellular pathogens use complex and tightly regulated processes to enter host cells. Upon initial interactions with signaling proteins at the surface of target cells, intracellular microbes activate and co-opt specific host signaling pathways that mediate cell surface–cytosol communications to facilitate pathogen internalization. Here, we discuss the roles of host receptor tyrosine kinases (RTKs) in the establishment of productive infections by major intracellular pathogens. We evaluate the gaps in the current understanding of this process and propose a comprehensive approach for assessing the role of host cell signaling in the biology of intracellular microorganisms and viruses. We also discuss RTK-targeting strategies for the treatment of various infections.

scholarly journals Drosophila fasciclin I is a novel homophilic adhesion molecule that along with fasciclin III can mediate cell sorting.

1990 ◽  
Vol 110 (5) ◽  
pp. 1825-1832 ◽  
Author(s):  
T Elkins ◽  
M Hortsch ◽  
A J Bieber ◽  
P M Snow ◽  
C S Goodman
Keyword(s):  
Cell Adhesion ◽  
Adhesion Molecule ◽  
Cell Sorting ◽  
Cell Adhesion Molecule ◽  
Neuronal Development ◽  
Specific Cell ◽  
Drosophila S2 Cells ◽  
Mediate Cell ◽  
Homophilic Adhesion

Fasciclin I is a membrane-associated glycoprotein that is regionally expressed on a subset of fasciculating axons during neuronal development in insects; it is expressed on apposing cell surfaces, suggesting a role in specific cell adhesion. In this paper we show that Drosophila fasciclin I is a novel homophilic cell adhesion molecule. When the nonadhesive Drosophila S2 cells are transfected with the fasciclin I cDNA, they form aggregates that are blocked by antisera against fasciclin I. When cells expressing fasciclin I are mixed with cells expressing fasciclin III, another Drosophila homophilic adhesion molecule, the mixture sorts into aggregates homogeneous for either fasciclin I- or fasciclin III-expressing cells. The ability of these two novel adhesion molecules to mediate cell sorting in vitro suggests that they might play a similar role during neuronal development.

Spatially regulated expression of three receptor tyrosine kinase genes during gastrulation in the zebrafish

Development ◽  
1994 ◽  
Vol 120 (2) ◽  
pp. 287-299 ◽  
Author(s):  
Q. Xu ◽  
N. Holder ◽  
R. Patient ◽  
S.W. Wilson
Keyword(s):  
Tyrosine Kinases ◽  
Dorsal Side ◽  
Developmental Expression ◽  
Tail Bud ◽  
Regulation Of Expression ◽  
Entire Axis ◽  
Regulate Gene Expression ◽  
Spatial Regulation ◽  
Regulated Expression ◽  
Early Developmental

We describe the isolation and early developmental expression of three novel zebrafish genes (rtk1-3) that encode members of the eph family of receptor tyrosine kinases. At the onset of gastrulation, rtk1 is expressed in the shield region corresponding to the future dorsal side of the embryo. As gastrulation proceeds, both rtk1 and rtk2 are expressed within the axial hypoblast along the entire axis of the embryo. After the gastrula stage is complete, expression of both genes is maintained in precursor cells of the notochord in the tail bud but is downregulated in other regions of the axial hypoblast, rtk3 is expressed in anterior axial hypoblast including the ‘pillow’ at the anterior tip of the hypoblast and in paraxial tissue in posterior regions of the embryo. We show that the precise spatial regulation of expression of rtk genes, ntl and goosecoid along the anteroposterior axis is maintained in embryos that have no dorsoventral axis. This indicates that the mechanisms that regulate gene expression along the anteroposterior and dorsoventral axes of the hypoblast may be independent.

Impaired integrin-mediated signal transduction, altered cytoskeletal structure and reduced motility in Hck/Fgr deficient macrophages

1999 ◽  
Vol 112 (22) ◽  
pp. 4067-4078 ◽  
Author(s):  
P.W. Suen ◽  
D. Ilic ◽  
E. Caveggion ◽  
G. Berton ◽  
C.H. Damsky ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Subcellular Localization ◽  
Tyrosine Phosphorylation ◽  
Tyrosine Kinases ◽  
Double Mutant ◽  
Src Family Kinases ◽  
Wild Type ◽  
Associated Proteins ◽  
Coated Surfaces ◽  
Mutant Cells

Integrin-mediated adhesion of monocytes and macrophages initiates a signal transduction pathway that leads to actin cytoskeletal reorganization, cell migration and immunologic activation. This signaling pathway is critically dependent on tyrosine kinases. To investigate the role of the Src-family of tyrosine kinases in integrin signal transduction, we have examined the adhesive properties of macrophages isolated from hck-/-fgr-/- double knockout mice which lack two of the three predominant Src-family kinases expressed in myeloid cells. Previous examination of polymorphonuclear leukocytes from these animals indicated that these kinases were critical in initiating the actin cytoskeletal rearrangements that lead to respiratory burst and granule secretion following integrin ligation. Double mutant peritoneal exudate macrophages demonstrated markedly reduced tyrosine phosphorylation responses compared to wild-type cells following plating on fibronectin, collagen or vitronectin-coated surfaces. Tyrosine phosphorylation of several actin-associated proteins (cortactin, paxillin, and tensin), as well as the Syk and Pyk2 tyrosine kinases, were all significantly reduced in double mutant cells. The subcellular localization of focal-adhesion associated proteins was also dramatically altered in mutant macrophages cultured on fibronectin-coated surfaces. In wild-type cells, filamentous actin, paxillin, and talin were concentrated along leading edges of the plasma membrane, suggesting that these proteins contribute to cellular polarization during migration in culture. Double mutant cells failed to show the polarized subcellular localization of these proteins. Likewise, double mutant macrophages failed to form normal filopodia under standard culture conditions. Together, these signaling and cytoskeletal defects may contribute to the reduced motility observed in in vitro assays. These data provide biochemical and morphological evidence that the Src-family kinases Hck and Fgr are required for normal integrin-mediated signal transduction in murine macrophages.

The receptor tyrosine kinase EphB4 and ephrin-B ligands restrict angiogenic growth of embryonic veins in Xenopus laevis

Development ◽  
2000 ◽  
Vol 127 (2) ◽  
pp. 269-278 ◽  
Author(s):  
P.M. Helbling ◽  
D.M. Saulnier ◽  
A.W. Brandli
Keyword(s):  
Xenopus Laevis ◽  
Tyrosine Kinases ◽  
Dominant Negative ◽  
Receptor Expression ◽  
Signaling Systems ◽  
Xenopus Embryos ◽  
Ephb Receptor ◽  
Ephb Receptors ◽  
Vessel Development ◽  
Neural Crest Migration

The cues and signaling systems that guide the formation of embryonic blood vessels in tissues and organs are poorly understood. Members of the Eph family of receptor tyrosine kinases and their cell membrane-anchored ligands, the ephrins, have been assigned important roles in the control of cell migration during embryogenesis, particularly in axon guidance and neural crest migration. Here we investigated the role of EphB receptors and their ligands during embryonic blood vessel development in Xenopus laevis. In a survey of tadpole-stage Xenopus embryos for EphB receptor expression, we detected expression of EphB4 receptors in the posterior cardinal veins and their derivatives, the intersomitic veins. Vascular expression of other EphB receptors, including EphB1, EphB2 or EphB3, could however not be observed, suggesting that EphB4 is the principal EphB receptor of the early embryonic vasculature of Xenopus. Furthermore, we found that ephrin-B ligands are expressed complementary to EphB4 in the somites adjacent to the migratory pathways taken by intersomitic veins during angiogenic growth. We performed RNA injection experiments to study the function of EphB4 and its ligands in intersomitic vein development. Disruption of EphB4 signaling by dominant negative EphB4 receptors or misexpression of ephrin-B ligands in Xenopus embryos resulted in intersomitic veins growing abnormally into the adjacent somitic tissue. Our findings demonstrate that EphB4 and B-class ephrins act as regulators of angiogenesis possibly by mediating repulsive guidance cues to migrating endothelial cells.

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