Aberrant intracellular IGF-1R beta-subunit makes receptor knockout cells (IGF1R-/-) susceptible to oncogenic transformation.
Insulin-like growth factor 1 receptor (IGF-1R) is important for transformation of cells with cellular and viral oncogenes. This knowledge is mainly based on experiments on IGF-1R knockout mouse fibroblasts, which mostly are unable to transform after introduction of various oncogenes. Recently, we observed two variants of R- cells, one of which (R-s) surprisingly expresses the beta-subunit of IGF-1R whereas the other one (R-r) does not. Here we show that the beta-subunit is localized intracellularly and forms perinuclear aggregates. It expresses tyrosine kinase activity and appears to be crucial for cell survival since knockdown of it kills the R-s cells. H-RasV12 and/or polyoma middle T-antigen fail to transform R-r, whereas R- cells expressing the beta-subunit were transformed as assessed by formation of colonies in soft agar. The oncogenic transformation of R-s cells was, however, abrogated when the aberrant beta-subunit was knockdown by siRNA. The occurrence of intracellular IGF-1R, especially in tumor cells, has been widely reported but its function has not been understood. Our study provides evidence that it may be important for cell survival and transformation.
Natalishvili
Natalia
N
Department of Oncology and Pathology, CCK R8:04, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
Axelson
Magnus
M
Girnita
Leonard
L
Larsson
Olle
O
Vasilcanu
Daiana
D
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005453:Fluorescence; D055786:Gene Knockout Techniques; D006801:Humans; D051379:Mice; D018613:Microscopy, Confocal; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation; D017526:Receptor, IGF Type 1 / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017526:Receptor, IGF Type 1; D051058:Oncogene Protein v-akt; D048049:Extracellular Signal-Regulated MAP Kinases