Arrestin‐independent constitutive endocytosis of GPR125/ADGRA3

Abstract

The orphan receptor GPR125 (ADGRA3) belongs to subgroup III of the adhesion G protein−coupled receptor (aGPCR) family. aGPCRs, also known as class B2 GPCRs, share basic structural and functional properties with other GPCRs. Many of them couple to G proteins and activate G protein−dependent and −independent signaling pathways, but little is known about aGPCR internalization and β-arrestin recruitment. GPR125 was originally described as a spermatogonial stem cell marker and studied for its role in Wnt signaling and cell polarity. Here, using cell-based assays and confocal microscopy, we show that GPR125 is expressed on the cell surface and undergoes constitutive endocytosis in a β-arrestin−independent, but clathrin-dependent manner, as indicated by colocalization with transferrin receptor 1, an early endosome marker. These data support that the constitutive internalization of GPR125 contributes to its biological functions by controlling receptor surface expression and accessibility for ligands. Our study sheds light on a new property of aGPCRs, namely internalization; a property described to be important for signal propagation, signal termination, and desensitization of class A (rhodopsin-like) and B1 (VIP/secretin) GPCRs.

RNA sequencing‑based identification of potential targets in acute myeloid leukemia: A case report

“…Thus, it was proposed that these genes may serve as potentially novel biomarkers of AML, pending further validation in additional patients, and in vitro and in vivo experimental models of AML. ADGRA3, also known as GPR125 is an adhesion G-protein-coupled membrane receptor, which mediates downstream signaling pathways by activation of G proteins (22). With respect to the role of ADGRA3 in AML, it has been reported that its protein product, GPR125, is downregulated in AML, in contrast to the results of the present study, suggesting that the exact role of this gene in AML requires further study (23).…”

Arrestin-Dependent and -Independent Internalization of G Protein–Coupled Receptors: Methods, Mechanisms, and Implications on Cell Signaling

“…Other GPCRs also internalize constitutively without the need for arrestins, but their exact mechanisms are not defined. Using enzyme-linked immunosorbent assay (ELISA) and confocal microscopy, the orphan adhesion receptor ADGRA3 (previously called GPR125) was found to undergo rapid constitutive internalization in an arrestinindependent, but clathrin-dependent manner (Spiess et al, 2019). The internalized receptor colocalized with transferrin receptor 1 in early endosomes.…”

Gpr125 identifies myoepithelial progenitors at tips of lacrimal ducts and is essential for tear film

“…Though less well understood, recent discoveries of involvement of aGPCRs in human disease has produced a growing interest in their therapeutic potential (33). Although Gpr125 is an orphan receptor evidence has emerged recently suggesting a role in receptor trafficking and endosomal signaling (28).…”

“…Previous studies have highlighted Gpr125 as a marker of undifferentiated murine spermatogonial progenitors (23), documented its elevation in the choroid plexus following injury and correlated its high expression with both good and poor outcome in cancer (24)(25)(26). Ectopic expression of Gpr125 has shown that in zebrafish it modulates Wnt/planar cell polarity processes by interacting with the cytoplasmic adaptor Disheveled (Dsh), and in cultured cells undergoes constitutive clathrin-mediated internalization to endosomes (27,28). However, the physiological function of native Gpr125 has remained elusive.…”