Oncogenic PIK3CA corrupts growth factor signaling specificity

Oncogenic PIK3CA corrupts growth factor signaling specificity

Abstract Technical limitations have prevented understanding of how growth factor signals are encoded in distinct activity patterns of the phosphoinositide 3-kinase (PI3K)/AKT pathway, and how this is altered by oncogenic pathway mutations. We introduce a kinetic, single-cell framework for precise ca...

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Main Authors: Ralitsa R Madsen, Alix Le Marois, Oliwia N Mruk, Margaritis Voliotis, Shaozhen Yin, Jahangir Sufi, Xiao Qin, Salome J Zhao, Julia Gorczynska, Daniele Morelli, Lindsay Davidson, Erik Sahai, Viktor I Korolchuk, Christopher J Tape, Bart Vanhaesebroeck
Format: Article
Language:English
Published: Springer Nature 2024-12-01
Series:Molecular Systems Biology
Subjects:
PI3K Signaling Dynamics
Information Transfer
Growth Factor Specificity
Single-cell Biology
Online Access:https://doi.org/10.1038/s44320-024-00078-x
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Summary:Abstract Technical limitations have prevented understanding of how growth factor signals are encoded in distinct activity patterns of the phosphoinositide 3-kinase (PI3K)/AKT pathway, and how this is altered by oncogenic pathway mutations. We introduce a kinetic, single-cell framework for precise calculations of PI3K-specific information transfer for different growth factors. This features live-cell imaging of PI3K/AKT activity reporters and multiplexed CyTOF measurements of PI3K/AKT and RAS/ERK signaling markers over time. Using this framework, we found that the PIK3CA H1047R oncogene was not a simple, constitutive activator of the pathway as often presented. Dose-dependent expression of PIK3CA H1047R in human cervical cancer and induced pluripotent stem cells corrupted the fidelity of growth factor-induced information transfer, with preferential amplification of epidermal growth factor receptor (EGFR) signaling responses compared to insulin-like growth factor 1 (IGF1) and insulin receptor signaling. PIK3CA H1047R did not only shift these responses to a higher mean but also enhanced signaling heterogeneity. We conclude that oncogenic PIK3CA H1047R corrupts information transfer in a growth factor-dependent manner and suggest new opportunities for tuning of receptor-specific PI3K pathway outputs for therapeutic benefit.
ISSN:1744-4292

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