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Somatostatin receptor 2A (Sst2A) agonists are the primary pharmacological treatment for growth hormone (GH) secreting pituitary tumors to inhibit GH secretion and limit the destructive effects of these tumors. Sst2A agonists are also widely used as imaging agents for neuroendocrine tumors, and are under investigation for treatment of these cancers. However, despite the clinical importance of Sst2A agonists, regulatory mechanisms controlling Sst2A internalization and signaling are not fully understood. Sst2A contains a C-terminal PDZ binding site that serves as a docking platform for PDZ domain containing proteins. In an unbiased screen for PDZ domain proteins that can interact with Sst2A, we identified Synaptojanin 2 binding protein (SYNJ2BP) / Outer mitochondrial protein 25 (OMP25). SYNJ2BP is an outer mitochondrial protein that has been shown previously to promote the internalization of the Activin Type II receptor. We find that SYNJ2BP interacts with Sst2A in a ligand-dependent manner. Importantly, we show that SYNJ2BP promotes interaction of Sst2A with the G protein couple receptor kinase 2 (GRK2), and that siRNA-mediated knockdown of SYNJ2BP dramatically inhibits Sst2A phosphorylation by endogenous GRKs. Moreover, overexpression of SYNJ2BP strongly potentiates Sst2A phosphorylation on the GRK phosphorylation sites. Modulation of SYNJ2BP expression also regulates somatostatin-stimulated β-arrestin recruitment to the plasma membrane. Interestingly, in contrast to the large effects on Sst2A phosphorylation and β-arrestin recruitment, modulation of SYNJ2BP expression only caused a small change in ligand-stimulated receptor internalization. When we assessed downstream signaling, we found that SYNJ2BP overexpression potently stimulated receptor-dependent activation of ERK1/2, but had little effect on the ability of Sst2A to repress forskolin-stimulated cAMP production. Taken together, these data demonstrate for the first time that interaction of Sst2A with a PDZ domain protein affects receptor regulation and signaling. Because multiple PDZ domain containing proteins have been shown to interact with Sst2A, these data also suggest that interaction of Sst2A with this class of proteins may be an important regulatory mechanism to bias its function within the cell.

journal of the endocrine society

SAT-313 Synaptojanin 2 Binding Protein Is Required for Efficient Somatostatin Receptor 2A Phosphorylation by G Protein Coupled Receptor Kinases and Signaling to the ERK/MAPK Pathway