Balanced ubiquitination determines cellular responsiveness to extracellular stimuli.

Signal strength evoked by ligand stimulation is crucial for cellular responses such as fate decision, cell survival/death, secretion, and migration. For example, morphogens are secreted signaling molecules that form concentration gradients within tissues and induce distinct cell fates in a signal strength-dependent manner. In addition to extracellular ligand abundance, the sensitivity of signal-receiving cells to ligands also influences signal strength. Cell sensitivity to ligands is controlled at various levels: receptor presentation at the cell surface, positive/negative regulation of signal transduction, and target gene activation/repression. While the regulation of signal transduction and gene transcription is well studied, receptor presentation is still not fully understood. Recently, it was reported that cellular sensitivity to the Wingless (Wg)/Wnt morphogen is regulated by balanced ubiquitination and deubiquitination of its receptor Frizzled (Fz). In this review, we review how ubiquitination regulates receptor presentation at the cell surface for the detection of extracellular signal strength.