Author ORCID Identifier

0000-0003-2685-0217

Date of Graduation

5-2018

Document Type

Dissertation (PhD)

Program Affiliation

Cell and Regulatory Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Agnes Schonbrunn, PhD

Committee Member

Jeffrey Frost, PhD

Committee Member

Carmen Dessauer, PhD

Committee Member

Shane Cunha, PhD

Committee Member

Andrew Bean, PhD

Committee Member

Dianna Milewicz, MD, PhD

Abstract

Somatostatin receptor 2 (sst2) is a Gi-coupled G-protein coupled receptor that mediates many of somatostatin’s neuroendocrine actions. Sst2 is a clinically important GPCR as it is the drug target of somatostatin analogs such as octreotide, lanreotide, and pasireotide. Treatment with these agonists is the main medical approach to controlling excessive hormone secretion from neuroendocrine tumors. Activation of sst2 decreases hormone secretion by inhibiting cAMP production and decreasing intracellular calcium concentrations. In addition, treatment with somatostatin analogs has been shown to decrease tumor growth. Unfortunately, many patients will fail to respond to somatostatin analogs despite sst2 being present on their tumors. Understanding the signaling, trafficking, and regulation of sst2 is crucial to determine why many patients fail to respond to these agonists. As Postsynaptic density protein/Discs large-1/Zona occludens-1 (PDZ) domain interactions often regulate the trafficking and signaling potential of other GPCRs, we examined the role of the sst2 PDZ ligand and additional C-terminal residues in controlling its intracellular trafficking, signaling, and regulation. We determined that sst2 traffics from early endosomes to late endosomes and then on to the trans-golgi network (TGN). Trafficking from late endosomes to the TGN is dependent upon an intact C-terminal tail and the retromer complex of endosomal coat proteins. Additionally, removing either 3 or 10 C-terminal amino acids from sst2 alters the pathway through which sst2 recycles to the plasma membrane. We also determined that the expression of SHANK3, a PDZ domain containing protein, could alter the plasma membrane expression of sst2 indicating an important role in sst2 regulation. Overall, our results indicate that sst2 trafficking and regulation depends upon an intact PDZ ligand and C-terminal tail.

Keywords

somatostatin receptor, trafficking, retromer, PDZ proteins, SHANK proteins, Rab proteins

Available for download on Saturday, April 27, 2019

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