A model of the PI cycle reveals the regulating roles of lipid-binding proteins and pitfalls of using mosaic biological data

Abstract

the phosphatidylinositol (pi) cycle is central to eukaryotic cell signaling. its complexity, due to the number of reactions and lipid and inositol phosphate intermediates involved makes it difficult to analyze experimentally. computational modelling approaches are seen as a way forward to elucidate complex biological regulatory mechanisms when this cannot be achieved solely through experimental approaches. Whilst mathematical modelling is well established in informing biological systems, many models are often informed by data sourced from multiple unrelated cell types (mosaic data) or from purified enzyme data. In this work, we develop a model of the PI cycle informed by experimental and omics data taken from a single cell type, namely platelets. We were able to make a number of predictions regarding the regulation of pi cycle enzymes, the importance of the number of receptors required for successful GpcR signaling and the importance of lipid-and protein-binding proteins in regulating second messenger outputs. We then consider how pathway behavior differs, when fully informed by data for HeLa cells and show that model predictions remain consistent. However, when informed by mosaic experimental data model predictions greatly vary illustrating the risks of using mosaic datasets from unrelated cell types.

Machine Learning Reveals Lipidome Remodeling Dynamics in a Mouse Model of Ovarian Cancer

“…Another class of phospholipids that emerged as important were the phosphatidylinositols (PI). These lipids are the central actors in the PI and PIP 2 cycles underpinning several mammalian cell signaling pathways ( 32 ). There, PI is converted into phosphatidylinositol-4-phosphate (PI4P), which is further converted into phosphatidylinositol-4,5-bisphosphate (PIP 2 ) via various phosphokinases.…”

Machine Learning Reveals Lipidome Remodeling Dynamics in a Mouse Model of Ovarian Cancer

“…Another class of phospholipids that emerged as important were the phosphatidylinositols (PI). These lipids are the central actors in the PI and PIP 2 cycles, underpinning several mammalian cell signaling pathways . There, PI is converted into phosphatidylinositol-4-phosphate (PI4P), which is further converted into phosphatidylinositol-4,5-bisphosphate (PIP 2 ) via various phosphokinases.…”

“…These lipids are the central actors in the PI and PIP 2 cycles, underpinning several mammalian cell signaling pathways. 35 There, PI is converted into phosphatidylinositol-4-phosphate (PI4P), which is further converted into phosphatidylinositol-4,5-bisphosphate (PIP 2 ) via various phosphokinases. PIP2, on the other hand, is a component of the phosphatidylinositol 3-kinase (PI3K) pathway that has been extensively implicated in cancer.…”

Deciphering glycoprotein VI signalling in platelet activation

“…159 Mazet et al have described an ODE-based model on the phosphatidylinositol cycle and suggested that lipid-and protein-binding proteins help regulate PtdIns(4,5)P2 and InsP3 in GPCR signalling. 165 These studies have shown the potential of mathematical models in elucidating platelet signalling through the interplay of protein phosphorylation and phosphoinositide metabolism and predicting platelet homeostasis and activation. However, these models did not account for other phosphoinositide isomers.…”