Schematic representation of signal activation of human somatostatin receptor subtype-2 by membrane-displayed somatostatin. A. Overview of this study. Membrane-displayed somatostatin (cyclic peptide) activates human somatostatin receptor subtype-2, which is heterologously produced in yeast, and leads to the activation of chimeric Gα proteins, the mitogen-activated protein kinase cascade, and transcription factor Ste12p. Phosphorylated Ste12p induces the overexpression of enhanced green fluorescent protein by binding to a pheromone response element in the FUS1 promoter of pYEX-fet (signal detection plasmid) (Hara et al. 2012a). This expression allows monitoring and quantification of signal transduction by fluorescence. B. Functional domains encoded by the membrane-displayed somatostatin plasmid. After processing by the secretory pathway, the signal sequence and glycosylphosphatidylinositol (GPI) targeting sequence are cleaved, and the somatostatin sequence, with a free N-terminus is displayed on the plasma membrane by GPI covalently linked to the C-terminus. C. Amino-acid sequence of membrane-displayed somatostatin without FLAG tag.