The Hippo signaling pathway is an evolutionarily conserved mechanism that controls organ size in animals. Yorkie is well known as a transcriptional co-activator that functions downstream of the Hippo pathway to positively regulate transcription of genes that promote tissue growth. Recent studies have shown that increased myosin activity activates both Yorkie and its vertebrate orthologue YAP, resulting in increased nuclear localization and tissue growth. Here we show that Yorkie also can accumulate at the cell cortex in the apical junctional region. Moreover, Yorkie functions at the cortex to promote activation of myosin through a myosin regulatory light chain kinase, Stretchin-Mlck. This Yorkie function is not dependent on its transcriptional activity and is required for larval and adult tissues to achieve appropriate size. Based on these results, we suggest that Yorkie functions in a feedforward "amplifier" loop that promotes myosin activation, and thereby greater Yorkie activity, in response to tension.

The Hippo pathway regulates tissue growth in many animals. Multiple upstream components promote Hippo pathway activity, but the organization of these different inputs, the degree of crosstalk between them, and whether they are regulated in a distinct manner is not well understood. Kibra activates the Hippo pathway by recruiting the core Hippo kinase cassette to the apical cortex. Here we show that the Hippo pathway downregulates Drosophila Kibra levels independently of Yorkie-mediated transcription. We find that Hippo signaling complex formation promotes Kibra degradation via SCFSlimb-mediated ubiquitination, that this effect requires Merlin, Salvador, Hippo, and Warts, and that this mechanism functions independently of other upstream Hippo pathway activators. Moreover, Kibra degradation appears patterned by differences in mechanical tension across the wing. We propose that Kibra degradation mediated by Hippo pathway components and regulated by cytoskeletal tension serves to control Kibra-driven Hippo pathway activation and ensure optimally scaled and patterned tissue growth.

During development, transcriptional complexes at enhancers regulate gene expression in complex spatiotemporal patterns. To achieve robust expression without spurious activation, the affinity and specificity of transcription factor–DNA interactions must be precisely balanced. Protein–protein interactions among transcription factors are also critical, yet how their affinities impact enhancer output is not understood. The Drosophila transcription factor Yan provides a well-suited model to address this, as its function depends on the coordinated activities of two independent and essential domains: the DNA-binding ETS domain and the self-associating SAM domain. To explore how protein–protein affinity influences Yan function, we engineered mutants that increase SAM affinity over four orders of magnitude. This produced a dramatic subcellular redistribution of Yan into punctate structures, reduced repressive output and compromised survival. Cell-type specification and genetic interaction defects suggest distinct requirements for polymerization in different regulatory decisions. We conclude that tuned protein–protein interactions enable the dynamic spectrum of complexes that are required for proper regulation.

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