Predicted 'wiring landscape' of Ras-effector interactions in 29 human tissues

Area of Science:

• Cellular signaling and molecular biology
• Systems biology and bioinformatics
• Proteomics and human tissue analysis

Background:

• Ras proteins are central signaling hubs at the plasma membrane, interacting with effectors in a mutually exclusive manner.
• Competition for binding at Ras hubs modulates downstream pathway activation, highlighting the importance of binding dynamics.

Purpose of the Study:

• To quantify Ras-effector complex amounts and characterize tissue-specific Ras 'wiring landscapes'.
• To simulate network reconfigurations induced by Ras mutations or stimuli and assess their impact.
• To identify effectors whose Ras complex formation is dependent on recruitment to the plasma membrane.

Main Methods:

• Utilized a mechanistic modeling approach integrating high-quality proteomic data from Ras and 56 effectors across 29 human tissues.
• Quantified individual Ras-effector complex amounts and determined tissue-specific Ras interaction networks.
• Simulated network changes under mutant and stimulus conditions, with a case study on epithelial tissues.

Main Results:

• Identified nine key effectors forming significant complexes with Ras in at least one of the 29 tissues.
• Characterized distinct, tissue-specific Ras 'wiring landscapes' based on proteomic data.
• Revealed 32 effectors requiring additional plasma membrane recruitment for significant complex formation with Ras.

Conclusions:

• Ras-effector binding dynamics are highly context-dependent, varying significantly across different human tissues.
• Tissue-specific interactions at the Ras signaling hub are crucial for determining downstream signaling outcomes.
• The study emphasizes the importance of the cellular microenvironment in regulating Ras pathway activity.