Signal Transduction

Signal transduction comprises the processes by which cells sense extracellular cues, convert them into intracellular messages and elicit appropriate responses, often culminating in changes in gene expression, metabolism or cell behaviour. At its core are receptors—transmembrane proteins that bind specific ligands and undergo conformational change—followed by sequential activation of intracellular mediators such as heterotrimeric G-proteins, protein kinases and second messengers (for example cyclic adenosine monophosphate). Phosphorylation and dephosphorylation, as well as cycles of nucleotide binding and hydrolysis, provide the means to switch individual proteins between active and inactive states. Networks of these molecular switches form cascades that amplify weak inputs, integrate multiple signals through branching and feedback, and generate sharp thresholds or oscillations. This organisation enables cells to filter noise, coordinate fate decisions and regulate fundamental processes from development to homeostatic maintenance. Dysregulation of signal transduction underlies numerous pathologies, including cancer, metabolic disorders and neurodegeneration, making its components major targets for therapeutic intervention.

Research from Nature Portfolio

Investigations into Hedgehog signalling have identified the endocytic adaptor Numb as a key regulator at the ciliary pocket. Numb binds the extracellular domain of Patched 1 following ligand engagement, promoting its clathrin-mediated removal from the primary cilium and enabling Smoothened activation. Loss of Numb in neural progenitors impairs Sonic Hedgehog-driven gene transcription and diminishes proliferation of cerebellar precursors, pinpointing a novel control point in morphogen gradient interpretation. In canonical Wnt signalling, a trimeric deubiquitylase complex—USP46, UAF1 and WDR20—has been shown to stabilise the Wnt co-receptor LRP6 by removing ubiquitin chains that would otherwise trigger its internalisation. Cells deficient in USP46 exhibit reduced LRP6 at the membrane, blunted β-catenin activity and compromised organoid viability, highlighting deubiquitylation as a rheostat for receptor availability. Studies of Rho GTPase networks have revealed that Rac activity at nascent protrusions recruits Lbc-type guanine nucleotide exchange factors Arhgef11 and Arhgef12, which in turn locally activate Rho to coordinate retraction. This spatio-temporal crosstalk synchronises protrusion–retraction cycles and controls migration speed and directionality, providing mechanistic insight into how small GTPase modules generate robust motility.

Signal Transduction publication trend

The graph below shows the total number of articles in signal transduction across all publications each year (not limited to Nature Index journals).

Technical terms

Signal transduction: The cascade of molecular events by which an external stimulus is converted into an intracellular response.

G-protein-coupled receptor (GPCR): A seven-transmembrane-domain receptor that activates heterotrimeric G proteins upon ligand binding.

Second messenger: A small intracellular molecule (for example cAMP or IP₃) whose levels change in response to receptor activation.

Phosphorylation: Covalent attachment of a phosphate group to a protein, mediated by kinases, which regulates protein activity.

Deubiquitylation: Removal of ubiquitin from proteins by deubiquitylases, affecting receptor stability and signal propagation.

Mechanosensor: A protein (for example PIEZO1) that converts mechanical force into biochemical signalling.

Channel capacity: A measure of the maximum rate at which information can be reliably transmitted through a signalling pathway.

References

1. Numb positively regulates Hedgehog signaling at the ciliary pocket. Nature Communications (2024).
2. The USP46 complex deubiquitylates LRP6 to promote Wnt/β-catenin signaling. Nature Communications (2023).
3. Rho GTPase activity crosstalk mediated by Arhgef11 and Arhgef12 coordinates cell protrusion-retraction cycles. Nature Communications (2023).
4. Gβγ activates PIP2 hydrolysis by recruiting and orienting PLCβ on the membrane surface. Proceedings of the National Academy of Sciences of the United States of America (2023).
5. The MAPK/ERK channel capacity exceeds 6 bit/hour. PLOS Computational Biology (2023).
6. Dual inhibition of butyrylcholinesterase and p38α mitogen-activated protein kinase: A new approach for the treatment of Alzheimer's disease. Pharmacology & Therapeutics (2024).