Oncogenic targeting of an activated tyrosine kinase to the Golgi apparatus in a glioblastoma.
Activating oncogenic mutations of receptor tyrosine kinases (RTKs) have been reported in several types of cancers. In many cases, genomic rearrangements lead to the fusion of unrelated genes to the DNA coding for the kinase domain of RTKs. All RTK-derived fusion proteins reported so far display oligomerization sequences within the 5' fusion partners that are responsible for oncogenic activation. Here, we report a mechanism by which an altered RTK gains oncogenic potential in a glioblastoma cell line. A microdeletion on 6q21 results in the fusion of FIG, a gene coding for a Golgi apparatus-associated protein, to the kinase domain of the protooncogene c-ROS. The fused protein product FIG-ROS is a potent oncogene, and its transforming potential resides in its ability to interact with and become localized to the Golgi apparatus. Thus we have found a RTK fusion protein whose subcellular location leads to constitutive kinase activation and results in oncogenic transformation.
Charest
Alan
A
Center for Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. charest@mit.edu
Kheifets
Vicky
V
Park
Julie
J
Lane
Keara
K
McMahon
Kevin
K
Nutt
Cathy L
CL
Housman
David
D
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D002896:Chromosomes, Human, Pair 6; D019084:Fluorescent Antibody Technique, Indirect; D005909:Glioblastoma / Q000201:enzymology* / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000378:metabolism*; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry* / Q000378:metabolism*; D012190:Retroviridae / Q000235:genetics; D013347:Subcellular Fractions; D014407:Tumor Cells, Cultured; D014461:Ultracentrifugation
D015514:Oncogene Proteins, Fusion; D010455:Peptides; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D011505:Protein-Tyrosine Kinases; C062333:ROS1 protein, human; D020794:Receptor Protein-Tyrosine Kinases; C483813:Ros1 protein, mouse; C483815:Ros1 protein, rat