FIGURE 1: Models for the regulation of YAP localization and activity. Left panel: various upstream signals provide inputs that feed into the MST1/2 substrates, LATS1/2, to phosphorylate YAP at Ser127, leading to its binding to 14-3-3, which in turn retains YAP in the cytoplasm. Moreover, the subsequent phosphorylation of YAP by casein kinase 1δ/ε triggers the recruitment of the SCF^β-TRCP complex, which promotes YAP’s proteolytic ubiquitination under high cell density conditions. Right panel: low cell density promotes SKP2 to interact with and ubiquitinate YAP via the K63 linkage, leading to enhanced YAP-TEAD interaction and nuclear retention of YAP (upper); high cell density promotes OTUD1 to bind YAP and reverse its K63-linked ubiquitination, leading to cytoplasmic localization of YAP (lower).