Stabilization of the Ras oncoprotein by the insulin-like growth factor 1 receptor during anchorage-independent growth.
R- cells are 3T3 cells derived from mouse embryos with a targeted disruption of the type 1 insulin-like growth factor receptor (IGF-IR) genes. R- cells are refractory to transformation by a variety of viral and cellular oncogenes, including an activated Ras. R- cells stably transfected with an activated Ha-Ras (R-Ras cells) fail to form colonies in soft agar. An IGF-IR truncated at residue 1245 cannot transform R- cells, even when strongly overexpressed. However, the combination of the truncated IGF-IR and an activated Ras induces transformation of R- cells. We show here that the Ras oncoprotein is rapidly degraded when R-Ras cells are grown under anchorage-independent conditions and that signaling from the truncated IGF-IR stabilizes Ras. In monolayer cultures, Ras levels remain constant regardless of the presence or absence of IGF-IR signaling. These results directly explain why Ras cannot transform mouse embryo fibroblasts devoid of IGF-IR. They also suggest a more generalized, alternative mechanism for transformation by Ras and, implicitly, another possible way for targeting Ras in tumor cells.
Gatzka
M
M
Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania 19107, USA.
Prisco
M
M
Baserga
R
R
D016475:3T3 Cells / Q000502:physiology; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D015536:Down-Regulation; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D051379:Mice; D010750:Phosphoproteins / Q000502:physiology; D010766:Phosphorylation; D011102:Polyhydroxyethyl Methacrylate; D011506:Proteins / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000502:physiology*; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014170:Transformation, Genetic / Q000502:physiology*; D018631:ras Proteins / Q000378:metabolism / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D011506:Proteins; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D011102:Polyhydroxyethyl Methacrylate; D017526:Receptor, IGF Type 1; D018631:ras Proteins