Centrosomal targeting of tyrosine kinase activity does not enhance oncogenicity in chronic myeloproliferative disorders.
Constitutive tyrosine kinase activation by reciprocal chromosomal translocation is a common pathogenetic mechanism in chronic myeloproliferative disorders. Since centrosomal proteins have been recurrently identified as translocation partners of tyrosine kinases FGFR1, JAK2, PDGFRα and PDGFRβ in these diseases, a role for the centrosome in oncogenic transformation has been hypothesized. In this study, we addressed the functional role of centrosomally targeted tyrosine kinase activity. First, centrosomal localization was not routinely found for all chimeric fusion proteins tested. Second, targeting of tyrosine kinases to the centrosome by creating artificial chimeric fusion kinases with the centrosomal targeting domain of AKAP450 failed to enhance the oncogenic transforming potential in both Ba/F3 and U2OS cells, although phospho-tyrosine-mediated signal transduction pathways were initiated at the centrosome. We conclude that the centrosomal localization of constitutively activated tyrosine kinases does not contribute to disease pathogenesis in chronic myeloproliferative disorders.
Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center, DKFZ and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
T
T
Bochtler
M
M
Kirsch
B
B
Maier
J
J
Bachmann
U
U
Klingmüller
S
S
Anderhub
A D
AD
Ho
A
A
Krämer
D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D018385:Centrosome / Q000502:physiology*; D002908:Chronic Disease; D006801:Humans; D009196:Myeloproliferative Disorders / Q000150:complications*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000502:physiology; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D011993:Recombinant Fusion Proteins; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta