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A gain of function ...
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Chiara, FedericaUppsala universitet,Ludwiginstitutet för cancerforskning
(author)
A gain of function mutation in the activation loop of platelet-derived growth factor beta-receptor deregulates its kinase activity
- Article/chapterEnglish2004
Publisher, publication year, extent ...
Numbers
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LIBRIS-ID:oai:DiVA.org:uu-72770
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-72770URI
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https://doi.org/10.1074/jbc.M406051200DOI
Supplementary language notes
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Language:English
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Summary in:English
Part of subdatabase
Classification
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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The platelet-derived growth factor receptors (PDGFRs) are receptor tyrosine kinases implicated in multiple aspects of cell growth, differentiation, and survival. Recently, a gain of function mutation in the activation loop of the human PDGFRalpha has been found in patients with gastrointestinal stromal tumors. Here we show that a mutation in the corresponding codon in the activation loop of the murine PDGFRbeta, namely an exchange of asparagine for aspartic acid at amino acid position 849 (D849N), confers transforming characteristics to embryonic fibroblasts from mutant mice, generated by a knock-in strategy. By comparing the enzymatic properties of the wild-type versus the mutant receptor protein, we demonstrate that the D849N mutation lowers the threshold for kinase activation, causes a dramatic alteration in the pattern of tyrosine phosphorylation kinetics following ligand stimulation, and induces a ligand-independent phosphorylation of several tyrosine residues. These changes result in deregulated recruitment of specific signal transducers. The GTPase-activating protein for Ras (RasGAP), a negative regulator of the Ras mitogenic pathway, displayed a delayed binding to the mutant receptor. Moreover, we have observed enhanced ligand-independent ERK1/2 activation and an increased proliferation of mutant cells. The p85 regulatory subunit of the phosphatidylinositol 3 '-kinase was constitutively associated with the mutant receptor, and this ligand-independent activation of the phosphatidylinositol 3'-kinase pathway may explain the observed strong protection against apoptosis and increased motility in cellular wounding assays. Our findings support a model whereby an activating point mutation results in a deregulated PDGFRbeta with oncogenic predisposition.
Subject headings and genre
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1-Phosphatidylinositol 3-Kinase/metabolism
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Actins/metabolism
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Animals
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Apoptosis
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Asparagine/chemistry
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Aspartic Acid/chemistry
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Binding Sites
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COS Cells
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Cells; Cultured
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Dose-Response Relationship; Drug
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Enzyme Activation
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Fibroblasts/metabolism
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Flow Cytometry
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Genetic Vectors
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Humans
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Kinetics
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Mice
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Mice; Inbred C57BL
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Mice; Mutant Strains
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Mitogen-Activated Protein Kinase 1/metabolism
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Mitogen-Activated Protein Kinase 3/metabolism
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Mutation
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NIH 3T3 Cells
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Platelet-Derived Growth Factor/metabolism
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Point Mutation
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Protein Structure; Tertiary
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Protein-Serine-Threonine Kinases/metabolism
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Proto-Oncogene Proteins/metabolism
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Receptor; Platelet-Derived Growth Factor beta/*genetics/metabolism
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Research Support; Non-U.S. Gov't
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Signal Transduction
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Substrate Specificity
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Time Factors
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Tyrosine/chemistry
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Up-Regulation
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Wound Healing
Added entries (persons, corporate bodies, meetings, titles ...)
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Goumans, Marie-José
(author)
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Forsberg, HenrikUppsala universitet,Ludwiginstitutet för cancerforskning
(author)
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Åhgrén, AiveUppsala universitet,Ludwiginstitutet för cancerforskning
(author)
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Rasola, Andrea
(author)
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Aspenström, PontusUppsala universitet,Ludwiginstitutet för cancerforskning(Swepub:uu)pontaspe
(author)
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Wernstedt, ChristerUppsala universitet,Ludwiginstitutet för cancerforskning(Swepub:uu)chrisws
(author)
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Hellberg, CarinaUppsala universitet,Ludwiginstitutet för cancerforskning(Swepub:uu)cahel517
(author)
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Heldin, Carl-HenrikUppsala universitet,Ludwiginstitutet för cancerforskning(Swepub:uu)carlheld
(author)
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Heuchel, RainerUppsala universitet,Ludwiginstitutet för cancerforskning(Swepub:uu)rainheuc
(author)
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Uppsala universitetLudwiginstitutet för cancerforskning
(creator_code:org_t)
Related titles
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In:Journal of Biological Chemistry279:41, s. 42516-425270021-92581083-351X
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Chiara, Federica
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Goumans, Marie-J ...
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Forsberg, Henrik
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Åhgrén, Aive
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Rasola, Andrea
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Aspenström, Pont ...
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Wernstedt, Chris ...
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Hellberg, Carina
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Heldin, Carl-Hen ...
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Heuchel, Rainer
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