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Extracellular amino acids induce their uptake into yeast by binding a plasma membrane-localized receptor complex (SPS sensor), which results in the endoproteolytic activation of two latent transcription factors, triggering the expression of amino acid permease genes. Pfirrmann et al. (p. 3299-3309) show that the catalytic domain of the activating protease Ssy5 is inhibited by its noncovalently attached prodomain and that amino acid-induced signals target the prodomain for destruction by the 26S proteasome. The authors use these findings to design an artificial temperature-regulated protease as a signal input device to create a synthetic temperature-regulated signaling pathway.
Timely assembly and disassembly of focal adhesions (FAs) are critical for cell migration. Extracellular signal-regulated kinase (ERK) has a well-established role in FA disassembly, where it phosphorylates and activates calpain proteases that cleave Rho and cytoskeletal linkers, including talin. Surprisingly, Pullikuth and Catling (p. 3233-3248) now show that ERK activity is also required for FA assembly and maturation. In this context, ERK phosphorylates p190A RhoGAP, uncoupling it from Rho to allow Rho-dependent FA formation. By selecting distinct substrates, ERK oversees the beginnings and endings of FAs.
PHF8 is a histone demethylase belonging to the JmjC domain family of proteins. Fortschegger et al. (p. 3286-3298) show that PHF8 is recruited to a large number of human promoters through its PHD domain association with histone H3 trimethylated at lysine 4 (H3K4me3), a marker of active genes. Additionally, PHF8 associates with the C-terminal domain of the largest subunit of RNA polymerase II and functions as a transcriptional coactivator for a large class of transcriptional activators. PHF8 proteins carrying mutations associated with X-linked mental retardation and cleft lip/palate are devoid of such coactivation function. Therefore, PHF8 is a chromatin-modifying transcriptional coactivator whose disruption would lead to human disease.