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A gain of function mutation in the activation loop of platelet-derived growth factor beta-receptor deregulates its kinase activity

Chiara, Federica (författare)
Uppsala universitet,Ludwiginstitutet för cancerforskning
Goumans, Marie-José (författare)
Forsberg, Henrik (författare)
Uppsala universitet,Ludwiginstitutet för cancerforskning
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Åhgrén, Aive (författare)
Uppsala universitet,Ludwiginstitutet för cancerforskning
Rasola, Andrea (författare)
Aspenström, Pontus (författare)
Uppsala universitet,Ludwiginstitutet för cancerforskning
Wernstedt, Christer (författare)
Uppsala universitet,Ludwiginstitutet för cancerforskning
Hellberg, Carina (författare)
Uppsala universitet,Ludwiginstitutet för cancerforskning
Heldin, Carl-Henrik (författare)
Uppsala universitet,Ludwiginstitutet för cancerforskning
Heuchel, Rainer (författare)
Uppsala universitet,Ludwiginstitutet för cancerforskning
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 (creator_code:org_t)
2004
2004
Engelska.
Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 279:41, s. 42516-42527
  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
Stäng  
  • 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.

Nyckelord

1-Phosphatidylinositol 3-Kinase/metabolism
Actins/metabolism
Animals
Apoptosis
Asparagine/chemistry
Aspartic Acid/chemistry
Binding Sites
COS Cells
Cells; Cultured
Dose-Response Relationship; Drug
Enzyme Activation
Fibroblasts/metabolism
Flow Cytometry
Genetic Vectors
Humans
Kinetics
Mice
Mice; Inbred C57BL
Mice; Mutant Strains
Mitogen-Activated Protein Kinase 1/metabolism
Mitogen-Activated Protein Kinase 3/metabolism
Mutation
NIH 3T3 Cells
Platelet-Derived Growth Factor/metabolism
Point Mutation
Protein Structure; Tertiary
Protein-Serine-Threonine Kinases/metabolism
Proto-Oncogene Proteins/metabolism
Receptor; Platelet-Derived Growth Factor beta/*genetics/metabolism
Research Support; Non-U.S. Gov't
Signal Transduction
Substrate Specificity
Time Factors
Tyrosine/chemistry
Up-Regulation
Wound Healing

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