ERKシグナル伝達経路のリン酸化標的の可変閾値

科学分野:

• Molecular Biology; Cell Signaling; Proteomics

背景:

• The extracellular signal-regulated kinase (ERK) pathway regulates critical cell functions like proliferation and survival.; A known "Goldilocks effect" describes how different ERK activation levels elicit distinct cellular outcomes, but underlying mechanisms remain unclear.; Previous studies identified threshold responses at transcriptional and cellular levels, but not at the upstream phosphorylation events.

研究 の 目的:

• To investigate whether phosphorylation events within the ERK pathway exhibit threshold responses to varying signaling strengths.; To identify specific phosphorylation sites that respond nonlinearly to ERK activation levels.

主な方法:

• Utilized mass spectrometry-based phosphoproteomics to quantify phosphorylation changes in ERK pathway targets.; Correlated phosphorylation levels of pathway substrates with the occupancy of dual activating phosphosites on ERK (2P-ERK).

主要な成果:

• Most phosphorylation events demonstrated a linear response to ERK activation.; A subset of phosphorylation sites exhibited nonlinear responses, with low thresholds (10-40% 2P-ERK) or high thresholds (>60% 2P-ERK).; Low-threshold sites were identified on transcriptional repressors involved in proliferation, while high-threshold sites were found on DNA repair proteins.

結論:

• Signaling thresholds are present at the phosphoproteome level within the ERK pathway.; These threshold mechanisms provide a molecular basis for differential cellular responses to ERK signaling strength.; Phosphorylation occupancies revealed cell-state specific differences not evident from traditional inhibitor studies.