A single bacterial protein from *Salmonella* can trick a human enzyme into phosphorylating the wrong amino acid—and this hijacking drives infection. Cells rely on enzymes called kinases to add phosphate groups to specific amino acids—serine, threonine, or tyrosine—as a way to switch proteins on or off. For decades, biologists assumed each kinase was hardwired to target only one type of amino acid. The discovery that a *Salmonella* protein, SteE, forces the human kinase GSK3 to phosphorylate tyrosine instead of its usual serine/threonine targets overturns that assumption. This reprogramming is not a laboratory curiosity: it directly triggers the anti-inflammatory state that lets *Salmonella* survive inside host cells. This project will test whether other bacteria carry similar reprogramming proteins, and whether human cells themselves might use the same trick. If kinase reprogramming is a general mechanism, it would rewrite the textbook on cell signalling. The work is fundamental science—no immediate clinical application is promised. But understanding how a pathogen commandeers a host kinase could eventually point toward new ways to block infection, or toward synthetic proteins that deliberately redirect kinase activity for therapeutic ends.
View original technical description
This proposal stems from a remarkable phenomenon I discovered recently: the reprogramming of canonical kinase specificity to a different amino acid and substrate by a small non-enzymatic bacterial (Salmonella) virulence protein, SteE. Phosphorylation of serine (S), threonine (T) and tyrosine (Y) residues isa widespread regulatory system in cells that provides a vast and reversible expansion to proteome function. I found that SteE interacts with the well-characterised eukaryotic S/T kinase, GSK3, and that this causesGSK3 to phosphorylates Y residues on two non-canonical substrates: SteE and the host transcription factor STAT3.SteE phosphorylation is required for STAT3 phosphorylation by GSK3, and this drives anti-inflammatory macrophage polarisation and Salmonella virulence. Therefore, S/T kinase phospho-acceptor site reprogramming is both mechanistically feasible and biologically relevant yet only described for one example. New preliminary data suggests the existence of previously unstudied, putative, kinase reprogramming proteins that are encoded by diverse bacteria. I will study these to test the hypothesis that kinase reprogramming represents a more general mechanism that can change the phospho-acceptor site specificity of diverse eukaryotic kinases and decipher the molecular basis of reprogramming across different kinases. I will also investigate whether eukaryotic proteins have kinase reprogramming activity. In this way, I will challenge the dogma that assigns kinases as either S/T-directed or dual specificity (phosphorylatesS/T and Y) and anticipate identifying a group of S/T kinases that can phosphorylate Y residues only when bound by a regulatory protein. Finally, through directed evolution I aim to begin the design of synthetic kinase-altering proteins as this could revolutionise the development of kinase-based therapeutics. Overall, this work will change our understanding of kinase regulation during health and disease.
Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.
Is something wrong? Let us know