Objectives: Establish LTK cellular systems and define whether signalling depends on dimerization/interface integrity; generate interface-disrupting mutants and quantify their effects on activation and pathway output; map substrate motifs via quantitative phosphoproteomics; validate AfBP engagement; measure how interface-targeting ligands reshape signalling networks; provide a generalizable blueprint for extending interface-centric analysis to other dark-kinome RTKs.
Expected results: First mechanistic map of LTK; public phosphoproteomic and signalling dataset; a cellular engagement + pathway paper defining interface dependency and substrate specificity.
Secondments: KUL (Prof Derua): Phosphoproteomics optimisation and workflow refinement (M20–23; 4 months); AZ: MD simulations to interpret structural/dynamic determinants of LTK regulation (M31–33; 3 months).
Integration: Establishes the mechanistic basis of an understudied RTK; informs WP1/DC2 bisubstrate-probe design and provides structural/functional constraints for WP3 optimisation and WP4 comparative benchmarking.
Interdisciplinarity: Combines cell signalling, phosphoproteomics, chemical biology and computational biophysics.
