Projects per year
Abstract / Description of output
RAS-ERK (extracellular signal-regulated kinase) pathway signals are modulated by scaffold proteins that assemble the components of different kinase tiers into a sequential phosphorylation cascade. In the prevailing model scaffold proteins function as isolated entities, where the flux of phosphorylation events progresses downstream linearly, to achieve ERK phosphorylation. We show that different types of scaffold proteins, specifically KSR1 (kinase suppressor of Ras 1) and IQGAP1 (IQ motif-containing guanosine triphosphatase activating protein 1), can bind to each other, forming a complex whereby phosphorylation reactions occur across both species. MEK (mitogen-activated protein kinase kinase) bound to IQGAP1 can phosphorylate ERK docked at KSR1, a process that we have named "trans-phosphorylation." We also reveal that ERK trans-phosphorylation participates in KSR1-regulated adipogenesis, and it also underlies the modest cytotoxicity exhibited by KSR-directed inhibitors. Overall, we identify interactions between scaffold proteins and trans-phosphorylation as an additional level of regulation in the ERK cascade, with broad implications in signaling and the design of scaffold protein-aimed therapeutics.
Original language | English |
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Journal | Science Advances |
DOIs | |
Publication status | Published - 15 Feb 2023 |
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Dive into the research topics of 'Scaffold coupling: ERK activation by trans-phosphorylation across different scaffold protein species.'. Together they form a unique fingerprint.Projects
- 1 Finished
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High resolution metabolite and peptide mass spectrometry
Von Kriegsheim, A., Christophorou, M., Finch, A., Morton, N., Ponting, C. & Walmsley, S.
2/10/17 → 1/11/22
Project: Research
Equipment
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Institute for Genetics and Cancer Mass Spectrometry Facility
Alex Von Kriegsheim (Manager)
Deanery of Molecular, Genetic and Population Health SciencesFacility/equipment: Facility