Interrogating the molecular mechanism of signal transduction in the TGF-β receptor superfamily

Abstract

A major unanswered question in cellular signalling is how binding of an extracellular ligand to its cell-surface receptor triggers activation of an intracellular signalling cascade to achieve a physiological response. TGF-β signalling is central to many physiological processes, from embryonic development to adult tissue homeostasis and immune responses. Over 30 dimeric growth factor ligands compete for binding to 7 type I receptors and 5 type II receptors, with the combinatorial nature of signalling complex formation enabling finely tuned signal integration. While existing structural data provide insights into the interactions between the extracellular domains of the receptors and their cognate growth factor ligands, it is not yet understood how the signal of ligand binding is relayed through the plasma membrane to activate the kinase domains. The answer may lie in the transmembrane and juxtamembrane regions which bridge the gap between ‘inside’ and ‘outside’ the cell. Here, I combine sequence conservation analysis, functional assays and structural approaches to try to build a picture of the molecular choreography of TGF-β signalling. These results lay the groundwork for future studies to unravel the molecular mechanisms of signal transduction in the TGF-β receptor superfamily and in single-pass transmembrane receptors more broadly, opening ways to modulate signalling pathways through novel approaches.