The Wnt pathway protein Dvl1 targets Somatostatin receptor 2 for lysosome-dependent degradation.
Journal of Biological Chemistry 2023 March 24
The Somatostatin receptor 2 (Sstr2) is a heterotrimeric G protein coupled receptor that is highly expressed in neuroendocrine tumors and is a common pharmacological target for intervention. Unfortunately, not all neuroendocrine tumors express Sstr2, and Sstr2 expression can be downregulated with prolonged agonist use. Sstr2 is rapidly internalized following agonist stimulation and, in the short term, is quantitatively recycled back to the plasma membrane. However, mechanisms controlling steady state expression of Sstr2 in the absence of agonist are less well described. Here we show that Sstr2 interacts with the Wnt pathway protein Dvl1 in a ligand-independent manner to target Sstr2 for lysosomal degradation. Interaction of Sstr2 with Dvl1 does not affect receptor internalization, recycling, or signaling to adenylyl cyclase, but does suppress agonist-stimulated ERK1/2 activation. Importantly, Dvl1-dependent degradation of Sstr2 can be stimulated by overexpression of Wnts, and treatment of cells with Wnt pathway inhibitors can boost Sstr2 expression in neuroendocrine tumor cells. Taken together, this study identifies for the first time a mechanism that targets Sstr2 for lysosomal degradation that is independent of Sstr2 agonist and can be potentiated by Wnt ligand. Intervention in this signaling mechanism has the potential to elevate Sstr2 expression in neuroendocrine tumors and enhance Sstr2-directed therapies.
Full text links
Trending Papers
Evidence-Based Guideline for the diagnosis and management of eosinophilic granulomatosis with polyangiitis.Nature Reviews. Rheumatology 2023 May 10
A Systematic Approach to Understanding Acid-Base Disorders in the Critically Ill.Annals of Pharmacotherapy 2023 April 27
Get seemless 1-tap access through your institution/university
For the best experience, use the Read mobile app
Read by QxMD is copyright © 2021 QxMD Software Inc. All rights reserved. By using this service, you agree to our terms of use and privacy policy.
Get seemless 1-tap access through your institution/university
For the best experience, use the Read mobile app