1. PIP 3 abundance overcomes PI3K signaling selectivity in invadopodia
- Author
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Charles T. Jakubik, Claire C. Weckerly, Gerald R.V. Hammond, Anne R. Bresnick, and Jonathan M. Backer
- Subjects
Class I Phosphatidylinositol 3-Kinases ,Biophysics ,Cell Biology ,Biochemistry ,Article ,Extracellular Matrix ,Diglycerides ,HEK293 Cells ,Gene Expression Regulation ,Phosphatidylinositol Phosphates ,Cell Movement ,Structural Biology ,Cell Line, Tumor ,Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases ,Mutation ,Podosomes ,Genetics ,Humans ,Female ,Mammary Glands, Human ,Molecular Biology ,Signal Transduction - Abstract
PI3Kβ is required for invadopodia-mediated matrix degradation by breast cancer cells. Invadopodia maturation requires GPCR activation of PI3Kβ and its coupling to SHIP2 to produce PI(3,4)P(2). We now test whether selectivity for PI3Kβ is preserved under conditions of mutational increases in PI3K activity. In breast cancer cells where PI3Kβ is inhibited, short chain diC8-PIP(3) rescues gelatin degradation in a SHIP2-dependent manner; rescue by diC8-PI(3,4)P(2) is SHIP2-independent. Surprisingly, expression of either activated PI3Kβ or PI3Kα mutants rescued the effects of PI3Kβ inhibition. In both cases, gelatin degradation was SHIP2-dependent. These data confirm the requirement for PIP(3) conversion to PI(3,4)P(2) for invadopodia function, and suggest that selectivity for distinct PI3K isotypes may be obviated by mutational activation of the PI3K pathway.
- Published
- 2022
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