Understanding the molecular basis of regulation of class I PI3Ks by activation signals, oncogenic mutations, and post-translational modifications
Date
2022-12-22
Authors
Ranga Prasad, Harish
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Abstract
Class I Phosphoinostide-3 Kinases (PI3K) generate Phosphatidylinositol-3, 4, 5 Trisphosphate (PIP3), which regulates important cellular tasks such as proliferation, cell growth, survival and metabolism through membrane recruitment and activation of downstream targets that bear PIP3 recognizing domains. Misregulation of class I PI3K signaling is found in several human diseases, such as cancer, immunological disorders, neurological disorders, diabetes, localized tissue overgrowth, and cardiovascular disease. Due to the essential roles of class I PI3Ks, their activity is held under tight control through molecular interactions with various activating partners and post- translational modifications (PTM). The aim of my thesis is to study the regulation of class I PI3Ks by activation signals, post-translational modifications (PTM), and oncogenic mutations. To this end, we have utilized a combination of cutting-edge biophysical and biochemical techniques like Hydrogen- Deuterium Exchange Mass Spectrometry (HDX-MS), lipid kinase assays and protein- lipid Fluorescence Resonance Energy Transfer (FRET) assays. Our results provide insights into novel aspects of regulation of PI3Kα by oncogenic mutations and the role of PTMs in modulating the activity of PI3Kγ. This work provides an excellent framework for understanding how PI3Ks are involved in human
diseases.
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Keywords
HDX-MS, PIK3CA, PIK3CG, class I PI3K