The Experts below are selected from a list of 55923 Experts worldwide ranked by ideXlab platform
Mireia Duñach - One of the best experts on this subject based on the ideXlab platform.
-
p120 Catenin-associated Fer and Fyn Tyrosine Kinases regulate β-catenin Tyr-142 phosphorylation and β-catenin-α-catenin interaction
Molecular and Cellular Biology, 2003Co-Authors: Jose Piedra, Susana Miravet, Julio Castaño, Héctor G. Pálmer, Nora Heisterkamp, Antonio García De Herreros, Mireia DuñachAbstract:β-Catenin has a key role in the formation of adherens junction through its interactions with E-cadherin and α-catenin. We show here that interaction of β-catenin with α-catenin is regulated by the phosphorylation of β-catenin Tyr-142. This residue can be phosphorylated in vitro by Fer or Fyn Tyrosine Kinases. Transfection of these Kinases to epithelial cells disrupted the association between both catenins. We have also examined whether these Kinases are involved in the regulation of this interaction by K-ras. Stable transfectants of the K-ras oncogene in intestinal epithelial IEC18 cells were generated which show little α-catenin-β-catenin association with respect to control clones; this effect is accompanied by increased Tyr-142 phosphorylation and activation of Fer and Fyn Kinases. As reported for Fer, Fyn kinase is constitutively bound to p120 catenin; expression of K-ras induces the phosphorylation of p120 catenin on Tyrosine residues increasing its affinity for E-cadherin and, consequently, promotes the association of Fyn with the adherens junction complex. Yes Tyrosine kinase also binds to p120 catenin but only upon activation, and stimulates Fer and Fyn Tyrosine Kinases. These results indicate that p120 catenin acts as a docking protein facilitating the activation of Fer/Fyn Tyrosine Kinases by Yes and demonstrate the role of these p120 catenin-associated Kinases in the regulation of β-catenin-α-catenin interaction.
Jose Piedra - One of the best experts on this subject based on the ideXlab platform.
-
p120 Catenin-associated Fer and Fyn Tyrosine Kinases regulate β-catenin Tyr-142 phosphorylation and β-catenin-α-catenin interaction
Molecular and Cellular Biology, 2003Co-Authors: Jose Piedra, Susana Miravet, Julio Castaño, Héctor G. Pálmer, Nora Heisterkamp, Antonio García De Herreros, Mireia DuñachAbstract:β-Catenin has a key role in the formation of adherens junction through its interactions with E-cadherin and α-catenin. We show here that interaction of β-catenin with α-catenin is regulated by the phosphorylation of β-catenin Tyr-142. This residue can be phosphorylated in vitro by Fer or Fyn Tyrosine Kinases. Transfection of these Kinases to epithelial cells disrupted the association between both catenins. We have also examined whether these Kinases are involved in the regulation of this interaction by K-ras. Stable transfectants of the K-ras oncogene in intestinal epithelial IEC18 cells were generated which show little α-catenin-β-catenin association with respect to control clones; this effect is accompanied by increased Tyr-142 phosphorylation and activation of Fer and Fyn Kinases. As reported for Fer, Fyn kinase is constitutively bound to p120 catenin; expression of K-ras induces the phosphorylation of p120 catenin on Tyrosine residues increasing its affinity for E-cadherin and, consequently, promotes the association of Fyn with the adherens junction complex. Yes Tyrosine kinase also binds to p120 catenin but only upon activation, and stimulates Fer and Fyn Tyrosine Kinases. These results indicate that p120 catenin acts as a docking protein facilitating the activation of Fer/Fyn Tyrosine Kinases by Yes and demonstrate the role of these p120 catenin-associated Kinases in the regulation of β-catenin-α-catenin interaction.
Tony Pawson - One of the best experts on this subject based on the ideXlab platform.
-
the discoidin domain receptor Tyrosine Kinases are activated by collagen
Molecular Cell, 1997Co-Authors: Wolfgang Vogel, Gerrald D Gish, Tony PawsonAbstract:Abstract Two mammalian receptor Tyrosine Kinases (DDR1 and DDR2) have extracellular domains closely related to a D. discoideum lectin, discoidin, required for cell aggregation. Here, we show that the mammalian DDR receptors bind and are activated by specific types of collagen. Stimulation of DDR receptor Tyrosine kinase activity requires the native triple-helical structure of collagen and occurs over an extended period of time. Collagen activation of DDR1 induces phosphorylation of a docking site for the Shc phosphoTyrosine binding domain, whose presence is controlled by alternative splicing. Activation of DDR2 by collagen results in the up-regulation of matrix metalloproteinase-1 expression. These results suggest that the discoidin-related DDR Tyrosine Kinases are novel collagen receptors with the potential to control cellular responses to the extracellular matrix.
-
sh2 sh3 adaptor proteins can link Tyrosine Kinases to a ste20 related protein kinase hpk1
Journal of Biological Chemistry, 1997Co-Authors: Mordechai Anafi, Tony Pawson, Friedemann Kiefer, Gerald D Gish, Geraldine Mbamalu, Norman N IscoveAbstract:Ste20-related protein Kinases have been implicated as regulating a range of cellular responses, including stress-activated protein kinase pathways and the control of cytoskeletal architecture. An important issue involves the identities of the upstream signals and regulators that might control the biological functions of mammalian Ste20-related protein Kinases. HPK1 is a protein-serine/threonine kinase that possesses a Ste20-like kinase domain, and in transfected cells activates a protein kinase pathway leading to the stress-activated protein kinase SAPK/JNK. Here we have investigated candidate upstream regulators that might interact with HPK1. HPK1 possesses an N-terminal catalytic domain and an extended C-terminal tail with four proline-rich motifs. The SH3 domains of Grb2 bound in vitro to specific proline-rich motifs in the HPK1 tail and functioned synergistically to direct the stable binding of Grb2 to HPK1 in transfected Cos1 cells. Epidermal growth factor (EGF) stimulation did not affect the binding of Grb2 to HPK1 but induced recruitment of the Grb2.HPK1 complex to the autophosphorylated EGF receptor and to the Shc docking protein. Several activated receptor and cytoplasmic Tyrosine Kinases, including the EGF receptor, stimulated the Tyrosine phosphorylation of the HPK1 serine/threonine kinase. These results suggest that HPK1, a mammalian Ste20-related protein-serine/threonine kinase, can potentially associate with protein-Tyrosine Kinases through interactions mediated by SH2/SH3 adaptors such as Grb2. Such interaction may provide a possible mechanism for cross-talk between distinct biochemical pathways following the activation of Tyrosine Kinases.
-
ligands for eph related receptor Tyrosine Kinases that require membrane attachment or clustering for activity
Science, 1994Co-Authors: Samuel Davis, Tony Pawson, Nicholas W Gale, Thomas H Aldrich, Peter C Maisonpierre, Vladimir Lhotak, Mitchell Goldfarb, George D YancopoulosAbstract:The EPH-related transmembrane Tyrosine Kinases constitute the largest known family of receptor-like Tyrosine Kinases, with many members displaying specific patterns of expression in the developing and adult nervous system. A family of cell surface-bound ligands exhibiting distinct, but overlapping, specificities for these EPH-related Kinases was identified. These ligands were unable to act as conventional soluble factors. However, they did function when presented in membrane-bound form, suggesting that they require direct cell-to-cell contact to activate their receptors. Membrane attachment may serve to facilitate ligand dimerization or aggregation, because antibody-mediated clustering activated previously inactive soluble forms of these ligands.
-
sh2 containing phosphoTyrosine phosphatase as a target of protein Tyrosine Kinases
Science, 1993Co-Authors: Gensheng Feng, Chichung Hui, Tony PawsonAbstract:A mouse phosphoTyrosine phosphatase containing two Src homology 2 (SH2) domains, Syp, was identified. Syp bound to autophosphorylated epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) receptors through its SH2 domains and was rapidly phosphorylated on Tyrosine in PDGF- and EGF-stimulated cells. Furthermore, Syp was constitutively phosphorylated on Tyrosine in cells transformed by v-src. This mammalian phosphatase is most closely related, especially in its SH2 domains, to the corkscrew (csw) gene product of Drosophila, which is required for signal transduction downstream of the Torso receptor Tyrosine kinase. The Syp gene is widely expressed throughout embryonic mouse development and in adult tissues. Thus, Syp may function in mammalian embryonic development and as a common target of both receptor and nonreceptor Tyrosine Kinases.
-
shc proteins are phosphorylated and regulated by the v src and v fps protein Tyrosine Kinases
Proceedings of the National Academy of Sciences of the United States of America, 1992Co-Authors: J Mcglade, Alec M Cheng, G Pelicci, Pier Giuseppe Pelicci, Tony PawsonAbstract:Abstract The mammalian shc gene encodes two overlapping proteins of 46 and 52 kDa, each with a C-terminal Src homology 2 (SH2) domain and an N-terminal glycine/proline-rich sequence, that induce malignant transformation when overexpressed in mouse fibroblasts. p46shc, p52shc, and an additional 66-kDa shc gene product become highly Tyrosine phosphorylated in Rat-2 cells transformed by the v-src or v-fps oncogene. Experiments using temperature-sensitive v-src and v-fps mutants indicate that Shc Tyrosine phosphorylation is rapidly induced upon activation of the v-Src or v-Fps Tyrosine Kinases. These results suggest that Shc proteins may be directly phosphorylated by the v-Src and v-Fps oncoproteins in vivo. In cells transformed by v-src or v-fps, or in normal cells stimulated with epidermal growth factor, Shc proteins complex with a poorly phosphorylated 23-kDa polypeptide (p23). Activated Tyrosine Kinases therefore regulate the association of Shc proteins with p23 and may thereby control the stimulation of an Shc-mediated signal transduction pathway. The efficient phosphorylation of Shc proteins and the apparent induction of their p23-binding activity in v-src- and v-fps-transformed cells are consistent with the proposition that the SH2-containing Shc polypeptides are biologically relevant substrates of the oncogenic v-Src and v-Fps Tyrosine Kinases.
Yosef Yarden - One of the best experts on this subject based on the ideXlab platform.
-
Regulation of MAPKs by growth factors and receptor Tyrosine Kinases
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2007Co-Authors: Menachem Katz, Ido Amit, Yosef YardenAbstract:Multiple growth- and differentiation-inducing polypeptide factors bind to and activate transmembrane receptors Tyrosine Kinases (RTKs), to instigate a plethora of biochemical cascades culminating in regulation of cell fate. We concentrate on the four linear mitogen-activated protein kinase (MAPK) cascades, and highlight organizational and functional features relevant to their action downstream to RTKs. Two cellular outcomes of growth factor action, namely proliferation and migration, are critically regulated by MAPKs and we detail the underlying molecular mechanisms. Hyperactivation of MAPKs, primarily the Erk pathway, is a landmark of cancer. We describe the many links of MAPKs to tumor biology and review studies that identified machineries permitting prolongation of MAPK signaling. Models attributing signal integration to both phosphorylation of MAPK substrates and to MAPK-regulated gene expression may shed light on the remarkably diversified functions of MAPKs acting downstream to activated RTKs.
-
Endocytosis of receptor Tyrosine Kinases is driven by monoubiquitylation, not polyubiquitylation.
The Journal of biological chemistry, 2003Co-Authors: Yaron Mosesson, Menachem Katz, Keren Shtiegman, Yaara Zwang, Gyorgi Vereb, János Szöllosi, Yosef YardenAbstract:Growth factors stimulate specific receptor Tyrosine Kinases, but subsequent receptor endocytosis terminates signaling. The ubiquitin ligase c-Cbl targets epidermal growth factor receptors (EGFRs) to endocytosis by tagging them with multiple ubiquitin molecules. However, the type of ubiquitylation is unknown; whereas polyubiquitin chains signal proteasomal degradation, ubiquitin monomers control other processes. We report that in isolation c-Cbl mediates monoubiquitylation rather than polyubiquitylation of EGFRs. Consistent with the sufficiency of monoubiquitylation, when fused to the tail of EGFR, a single ubiquitin induces receptor endocytosis and degradation in cells. By using receptor and ubiquitin mutants, we infer that c-Cbl attaches a founder monoubiquitin to the kinase domain of EGFR and this is complemented by the conjugation of additional monoubiquitins. Hence, receptor Tyrosine Kinases are desensitized through conjugation of multiple monoubiquitins, which is distinct from polyubiquitin-dependent proteasomal degradation.
-
molecular mechanisms underlying endocytosis and sorting of erbb receptor Tyrosine Kinases
FEBS Letters, 2001Co-Authors: Hadassa Waterman, Yosef YardenAbstract:The major process that regulates the amplitude and kinetics of signal transduction by Tyrosine kinase receptors is endocytic removal of active ligand–receptor complexes from the cell surface, and their subsequent sorting to degradation or to recycling. Using the ErbB family of receptor Tyrosine Kinases we exemplify the diversity of the down regulation process, and concentrate on two sorting steps whose molecular details are emerging. These are the Eps15-mediated sorting to clathrin-coated regions of the plasma membrane and the c-Cbl-mediated targeting of receptors to lysosomal degradation. Like in yeast cells, sorting involves not only protein phosphorylation but also conjugation of ubiquitin molecules. The involvement of other molecules is reviewed and recent observations that challenge the negative regulatory role of endocytosis are described. Finally, we discuss the relevance of receptor down regulation to cancer therapy.
-
neu differentiation factor inhibits egf binding a model for trans regulation within the erbb family of receptor Tyrosine Kinases
Journal of Biological Chemistry, 1995Co-Authors: Devarajan Karunagaran, Eldad Tzahar, Yosef YardenAbstract:Abstract Neu differentiation factor (NDF, or heregulin) and epidermal growth factor (EGF) are structurally related proteins that bind to distinct members of the ErbB family of receptor Tyrosine Kinases. Here we show that NDF inhibits EGF binding in a cell type-specific manner. The inhibitory effect is distinct from previously characterized mechanisms that involve protein kinase C and receptor internalization because it occurred at 4°C and displayed reversibility. The extent of inhibition correlated with both receptor saturation and affinity of different NDF isoforms, and it was abolished upon overexpression of either EGF receptor or ErbB-2. Binding kinetics and equilibrium analyses indicated that NDF reduced the affinity, rather than the number, of EGF receptors, through an acceleration of the rate of ligand dissociation and deceleration of the association rate. On the basis of co-immunoprecipitation of EGF and NDF receptors, we attribute the inhibitory effect to the formation of receptor heterodimers. According to this model, EGF binding to NDF-occupied heterodimers is partially blocked. This model of negative trans-regulation within the ErbB family is relevant to other subgroups of receptor Tyrosine Kinases and may have physiological implications.
Antonio García De Herreros - One of the best experts on this subject based on the ideXlab platform.
-
p120 Catenin-associated Fer and Fyn Tyrosine Kinases regulate β-catenin Tyr-142 phosphorylation and β-catenin-α-catenin interaction
Molecular and Cellular Biology, 2003Co-Authors: Jose Piedra, Susana Miravet, Julio Castaño, Héctor G. Pálmer, Nora Heisterkamp, Antonio García De Herreros, Mireia DuñachAbstract:β-Catenin has a key role in the formation of adherens junction through its interactions with E-cadherin and α-catenin. We show here that interaction of β-catenin with α-catenin is regulated by the phosphorylation of β-catenin Tyr-142. This residue can be phosphorylated in vitro by Fer or Fyn Tyrosine Kinases. Transfection of these Kinases to epithelial cells disrupted the association between both catenins. We have also examined whether these Kinases are involved in the regulation of this interaction by K-ras. Stable transfectants of the K-ras oncogene in intestinal epithelial IEC18 cells were generated which show little α-catenin-β-catenin association with respect to control clones; this effect is accompanied by increased Tyr-142 phosphorylation and activation of Fer and Fyn Kinases. As reported for Fer, Fyn kinase is constitutively bound to p120 catenin; expression of K-ras induces the phosphorylation of p120 catenin on Tyrosine residues increasing its affinity for E-cadherin and, consequently, promotes the association of Fyn with the adherens junction complex. Yes Tyrosine kinase also binds to p120 catenin but only upon activation, and stimulates Fer and Fyn Tyrosine Kinases. These results indicate that p120 catenin acts as a docking protein facilitating the activation of Fer/Fyn Tyrosine Kinases by Yes and demonstrate the role of these p120 catenin-associated Kinases in the regulation of β-catenin-α-catenin interaction.
