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Robert Roskoski - One of the best experts on this subject based on the ideXlab platform.
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src Protein Tyrosine Kinase structure mechanism and small molecule inhibitors
Pharmacological Research, 2015Co-Authors: Robert RoskoskiAbstract:The physiological Src proto-oncogene is a Protein-Tyrosine Kinase that plays key roles in cell growth, division, migration, and survival signaling pathways. From the N- to C-terminus, Src contains a unique domain, an SH3 domain, an SH2 domain, a Protein-Tyrosine Kinase domain, and a regulatory tail. The chief phosphorylation sites of human Src include an activating pTyr419 that results from phosphorylation in the Kinase domain by an adjacent Src molecule and an inhibitory pTyr530 in the regulatory tail that results from phosphorylation by C-terminal Src Kinase (Csk) or Chk (Csk homologous Kinase). The oncogenic Rous sarcoma viral Protein lacks the equivalent of Tyr530 and is constitutively activated. Inactive Src is stabilized by SH2 and SH3 domains on the rear of the Kinase domain where they form an immobilizing and inhibitory clamp. Protein Kinases including Src contain hydrophobic regulatory and catalytic spines and collateral shell residues that are required to assemble the active enzyme. In the inactive enzyme, the regulatory spine contains a kink or a discontinuity with a structure that is incompatible with catalysis. The conversion of inactive to active Src is accompanied by electrostatic exchanges involving the breaking and making of distinct sets of Kinase domain salt bridges and hydrogen bonds. Src-catalyzed Protein phosphorylation requires the participation of two Mg(2+) ions. Although nearly all Protein Kinases possess a common K/E/D/D signature, each enzyme exhibits its unique variations of the Protein-Kinase reaction template. Bosutinib, dasatinib, and ponatinib are Src/multiKinase inhibitors that are approved by the FDA for the treatment of chronic myelogenous leukemia and vandetanib is approved for the treatment of medullary thyroid cancer. The Src and BCR-Abl inhibitors saracatinib and AZD0424, along with the previous four drugs, are in clinical trials for a variety of solid tumors including breast and lung cancers. Both ATP and targeted therapeutic Src Protein Kinase inhibitors such as dasatinib and ponatinib make hydrophobic contacts with catalytic spine residues and form hydrogen bonds with hinge residues connecting the small and large Kinase lobes.
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structure and regulation of kit Protein Tyrosine Kinase the stem cell factor receptor
Biochemical and Biophysical Research Communications, 2005Co-Authors: Robert RoskoskiAbstract:Abstract Signaling by stem cell factor and Kit, its receptor, play important roles in gametogenesis, hematopoiesis, mast cell development and function, and melanogenesis. Moreover, human and mouse embryonic stem cells express Kit transcripts. Stem cell factor exists as both a soluble and a membrane-bound glycoProtein while Kit is a glycoProtein receptor Protein-Tyrosine Kinase. The complete absence of stem cell factor or Kit is lethal. Gain-of-function mutations of Kit are associated with several human neoplasms including acute myelogenous leukemia, gastrointestinal stromal tumors, mastocytomas, and nasal T-cell lymphomas. Binding of stem cell factor to Kit results in receptor dimerization and activation of Protein Kinase activity. The activated receptor becomes autophosphorylated at Tyrosine residues that serve as docking sites for signal transduction molecules containing SH2 domains. Kit activates Akt, Src family Kinases, phosphatidylinositol 3-Kinase, phospholipase Cγ, and Ras/mitogen-activated Protein Kinases. Kit exists in active and inactive conformations as determined by X-ray crystallography. Kit consists of an extracellular domain, a transmembrane segment, a juxtamembrane domain, and a Protein Kinase domain that contains an insert of about 80 amino acid residues. The juxtamembrane domain inhibits enzyme activity in cis by maintaining the control αC-helix and the activation loop in their inactive conformations. The juxtamembrane domain also inhibits receptor dimerization. STI-571, a clinically effective targeted Protein-Tyrosine Kinase inhibitor, binds to an inactive conformation of Kit. The majority of human gastrointestinal stromal tumors have Kit gain-of-function mutations in the juxtamembrane domain, and most people with these tumors respond to STI-571. STI-571 binds to Kit and Bcr-Abl (the oncoProtein of chronic myelogenous leukemia) at their ATP-binding sites.
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src Protein Tyrosine Kinase structure and regulation
Biochemical and Biophysical Research Communications, 2004Co-Authors: Robert RoskoskiAbstract:Src and Src-family Protein Kinases are proto-oncogenes that play key roles in cell morphology, motility, proliferation, and survival. v-Src (a viral Protein) is encoded by the chicken oncogene of Rous sarcoma virus, and Src (the cellular homologue) is encoded by a physiological gene, the first of the proto-oncogenes. From the N- to C-terminus, Src contains an N-terminal 14-carbon myristoyl group, a unique segment, an SH3 domain, an SH2 domain, a Protein-Tyrosine Kinase domain, and a C-terminal regulatory tail. The chief phosphorylation sites of Src include Tyrosine 416 that results in activation from autophosphorylation and Tyrosine 527 that results in inhibition from phosphorylation by C-terminal Src Kinase. In the restrained state, the SH2 domain forms a salt bridge with phosphoTyrosine 527, and the SH3 domain binds to the Kinase domain via a polyproline type II left-handed helix. The SH2 and SH3 domains occur on the backside of the Kinase domain away from the active site where they stabilize a dormant enzyme conformation. Protein-Tyrosine phosphatases such as PTPalpha displace phosphoTyrosine 527 from the Src SH2 domain and mediate its dephosphorylation leading to Src Kinase activation. C-terminal Src Kinase consists of an SH3, SH2, and Kinase domain; it lacks an N-terminal myristoyl group and a C-terminal regulatory tail. Its X-ray structure has been determined, and the SH2 lobe occupies a position that is entirely different from that of Src. Unlike Src, the C-terminal Src Kinase SH2 and SH3 domains stabilize an active enzyme conformation. Amino acid residues in the alphaD helix near the catalytic loop in the large lobe of C-terminal Src Kinase serve as a docking site for the physiological substrate (Src) but not for an artificial substrate (polyGlu(4)Tyr).
Thomas Prebet - One of the best experts on this subject based on the ideXlab platform.
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Protein Tyrosine Kinase 7 has a conserved role in Wnt/β-catenin canonical signalling.
EMBO Reports, 2011Co-Authors: Francesca Puppo, Anne Catherine Lhoumeau, Sylvie Marchetto, Virginie Thomé, Marie Cibois, Akanksha Gangar, Frédérique Lembo, Edwige Belotti, Patrick Lecine, Thomas PrebetAbstract:The receptor Protein Tyrosine Kinase 7 (PTK7) was recently shown to participate in noncanonical Wnt/planar cell polarity signalling during mouse and frog embryonic development. In this study, we report that PTK7 interacts with β-catenin in a yeast two-hybrid assay and mammalian cells. PTK7-deficient cells exhibit weakened β-catenin/T-cell factor transcriptional activity on Wnt3a stimulation. Furthermore, Xenopus PTK7 is required for the formation of Spemann's organizer and for Siamois promoter activation, events that require β-catenin transcriptional activity. Using epistatic assays, we demonstrate that PTK7 functions upstream from glycogen synthase Kinase 3. Taken together, our data reveal a new and conserved role for PTK7 in the Wnt canonical signalling pathway.
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Protein Tyrosine Kinase 7 has a conserved role in Wnt/β‐catenin canonical signalling
EMBO Reports, 2010Co-Authors: Francesca Puppo, Anne Catherine Lhoumeau, Sylvie Marchetto, Virginie Thomé, Marie Cibois, Akanksha Gangar, Frédérique Lembo, Edwige Belotti, Patrick Lecine, Thomas PrebetAbstract:The receptor Protein Tyrosine Kinase 7 (PTK7) was recently shown to participate in noncanonical Wnt/planar cell polarity signalling during mouse and frog embryonic development. In this study, we report that PTK7 interacts with b-catenin in a yeast two-hybrid assay and mammalian cells. PTK7-deficient cells exhibit weakened b-catenin/T-cell factor transcriptional activity on Wnt3a stimulation. Furthermore, Xenopus PTK7 is required for the formation of Spemann’s organizer and for Siamois promoter activation, events that require b-catenin transcriptional activity. Using epistatic assays, we demonstrate that PTK7 functions upstream from glycogen synthase Kinase 3. Taken together, our data reveal a new and conserved role for PTK7 in the Wnt canonical signalling pathway.
Hirohei Yamamura - One of the best experts on this subject based on the ideXlab platform.
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structure and function of syk Protein Tyrosine Kinase
Journal of Biochemistry, 2001Co-Authors: Kiyonao Sada, Tomoko Takano, Shigeru Yanagi, Hirohei YamamuraAbstract:Non-receptor type of Protein-Tyrosine Kinase Syk contains 2 Src homology 2 (SH2) domains in tandem and multiple autophosphorylation sites. Syk is activated upon binding of tandem SH2 domains to immunoreceptor Tyrosine-based activating motif (ITAM) and plays an essential role in lymphocyte development and activation of immune cells. Syk is critical for Tyrosine phosphorylation of multiple Proteins which regulate important pathways leading from the receptor, such as Ca(2+) mobilization and mitogen-activated Protein Kinase (MAPK) cascades. Recent findings reveal that expression of Syk appears to be involved in a wide variety of cellular functions and pathogenesis of malignant cancer. These observations have demonstrated that Syk is a key molecule that controls multiple physiological functions in cells.
Francesca Puppo - One of the best experts on this subject based on the ideXlab platform.
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Protein Tyrosine Kinase 7 has a conserved role in Wnt/β-catenin canonical signalling.
EMBO Reports, 2011Co-Authors: Francesca Puppo, Anne Catherine Lhoumeau, Sylvie Marchetto, Virginie Thomé, Marie Cibois, Akanksha Gangar, Frédérique Lembo, Edwige Belotti, Patrick Lecine, Thomas PrebetAbstract:The receptor Protein Tyrosine Kinase 7 (PTK7) was recently shown to participate in noncanonical Wnt/planar cell polarity signalling during mouse and frog embryonic development. In this study, we report that PTK7 interacts with β-catenin in a yeast two-hybrid assay and mammalian cells. PTK7-deficient cells exhibit weakened β-catenin/T-cell factor transcriptional activity on Wnt3a stimulation. Furthermore, Xenopus PTK7 is required for the formation of Spemann's organizer and for Siamois promoter activation, events that require β-catenin transcriptional activity. Using epistatic assays, we demonstrate that PTK7 functions upstream from glycogen synthase Kinase 3. Taken together, our data reveal a new and conserved role for PTK7 in the Wnt canonical signalling pathway.
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Protein Tyrosine Kinase 7 has a conserved role in Wnt/β‐catenin canonical signalling
EMBO Reports, 2010Co-Authors: Francesca Puppo, Anne Catherine Lhoumeau, Sylvie Marchetto, Virginie Thomé, Marie Cibois, Akanksha Gangar, Frédérique Lembo, Edwige Belotti, Patrick Lecine, Thomas PrebetAbstract:The receptor Protein Tyrosine Kinase 7 (PTK7) was recently shown to participate in noncanonical Wnt/planar cell polarity signalling during mouse and frog embryonic development. In this study, we report that PTK7 interacts with b-catenin in a yeast two-hybrid assay and mammalian cells. PTK7-deficient cells exhibit weakened b-catenin/T-cell factor transcriptional activity on Wnt3a stimulation. Furthermore, Xenopus PTK7 is required for the formation of Spemann’s organizer and for Siamois promoter activation, events that require b-catenin transcriptional activity. Using epistatic assays, we demonstrate that PTK7 functions upstream from glycogen synthase Kinase 3. Taken together, our data reveal a new and conserved role for PTK7 in the Wnt canonical signalling pathway.
Mark E. Fortini - One of the best experts on this subject based on the ideXlab platform.
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signalling by the sevenless Protein Tyrosine Kinase is mimicked by rasl activation
Nature, 1992Co-Authors: Michael A. Simon, Mark E. Fortini, Gerald M. RubinAbstract:CELL-FATE specification of R7 photoreceptors in the developing Drosophila eye depends on an inductive signal from neighbouring R8 cells. Mutations in three genes, sevenless (sev), bride-of-sevenless (boss) and seven-in-absentia (sina) cause the R7 precursor to become a non-neural cone cell1–3. The sev gene encodes a receptor Protein Tyrosine Kinase (Sev) localized on the R7 surface, activated by a boss-encoded ligand presented by R8 (refs 4–6). The sina gene encodes a nuclear factor required in R7 (ref. 3). Reduction in the dosage of the Rasl gene impairs Sev-mediated signalling, suggesting that activation of Rasl may be an important consequence of Sev activation7. We report here that Rasl activation may account for all of the signalling action of Sev; an activated RaslVal12 Protein rescues the normal R7 precursor from transformation into a cone cell in sev and boss null mutants and induces the formation of supernumerary R7 cells. Similar activation of the Drosophila Ras2 Protein does not produce these effects, demonstrating Ras Protein specificity.
