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Activation of phosphatidylinositol 3-kinase in cells expressing abl oncogene variants
L Varticovski1, G Q Daley, P Jackson
1Department of Biomedical Research, St. Elizabeth's Hospital, Boston, Massachusetts 02135.
Abstract:
A phosphoinositide kinase specific for the D-3 position of the inositol ring, phosphatidylinositol (PI) 3-kinase, associates with activated receptors for platelet-derived growth factor, insulin, and colony-stimulating factor 1, with products of the oncogenes src, fms, yes, crk, and with polyomavirus middle T antigen. Efficient fibroblast transformation by proteins of the abl and src oncogene families requires activation of their protein-tyrosine kinase activity and membrane association via an amino-terminal myristoylation. We have demonstrated that the PI 3-kinase directly associates with autophosphorylated, activated protein-tyrosine kinase variants of the abl protein. In vivo, this association leads to accumulation of the highly phosphorylated products of PI 3-kinase, PI-3,4-bisphosphate and PI-3,4,5-trisphosphate, only in myristoylated, transforming abl protein variants. Myristoylation thus appears to be required to recruit PI 3-kinase activity to the plasma membrane for in vivo activation and correlates with the mitogenicity of the abl protein variants.
Insights
Phosphatidylinositol 3-kinase (PI 3-kinase) directly associates with activated abl protein variants. Myristoylation is crucial for recruiting PI 3-kinase to the plasma membrane, enabling abl protein-driven cell transformation.
Area of Science:
- Molecular Biology
- Cell Signaling
- Oncogenesis
Background:
- Phosphatidylinositol 3-kinase (PI 3-kinase) is a key enzyme in cell signaling pathways.
- Oncogenic proteins, such as abl, can drive cell transformation through aberrant signaling.
- Membrane association via myristoylation is essential for the transforming activity of some oncogenes.
Purpose of the Study:
- To investigate the direct association between PI 3-kinase and activated abl protein.
- To determine the role of myristoylation in the recruitment and activation of PI 3-kinase by abl variants.
- To understand the in vivo consequences of PI 3-kinase activation by myristoylated abl proteins.
Main Methods:
- Biochemical assays to detect PI 3-kinase association with abl protein variants.
- Analysis of in vivo phosphorylation of PI 3-kinase products (PI-3,4-bisphosphate and PI-3,4,5-trisphosphate).
- Comparison of transforming activity between myristoylated and non-myristoylated abl protein variants.
Main Results:
- Direct association was observed between PI 3-kinase and autophosphorylated, activated abl protein.
- Accumulation of PI-3,4-bisphosphate and PI-3,4,5-trisphosphate was detected specifically in myristoylated, transforming abl variants.
- Myristoylation was identified as a critical factor for recruiting PI 3-kinase to the plasma membrane for activation.
Conclusions:
- Myristoylation of abl protein is essential for recruiting PI 3-kinase activity to the plasma membrane.
- This recruitment leads to in vivo activation of PI 3-kinase and subsequent cell transformation.
- The findings highlight a critical mechanism linking oncogene activation, membrane targeting, and PI 3-kinase signaling in cancer progression.