The role of ADGRE5/CD97 in human retinal pigment epithelial cell growth and survival

Abstract

Cell surface molecules of retinal pigment epithelial (RPE) cells participate in the pathogenesis of retinal diseases. In an attempt to identify cell surface proteins that play a role in RPE cell–cell interactions, we have considered studying the expression, regulation, and signaling of ADGRE5/CD97, an adhesion G protein–coupled receptor family member, based on its known adhesive function in other cell types such as leukocytes. We showed that RPE cells express three isoforms of CD97 and identified inflammation‐related cytokines as important mediators regulating CD97 expression. Whereas TNF‐α and IFN‐γ upregulated CD97, TGF‐β decreased CD97 expression. Due to interaction with CD55, ARPE‐19 cells firmly adhered to monocytes and T lymphocytes when overexpressing CD97, suggesting a role for CD97 in controlling leukocyte infiltration across the RPE‐based blood–retinal barrier. CD97‐mediated signaling acted synergistically with PDGF‐BB and IFN‐γ to regulate cell growth and survival, ensuring a cellular balance under inflammatory conditions. These findings suggest that CD97 on RPE cells serves to control leukocyte activation and trafficking in uveoretinal inflammation while at the same time regulating second messenger‐mediated gene expression, cell growth, and survival.

The expression profile and tumorigenic mechanisms of CD97 (ADGRE5) in glioblastoma render it a targetable vulnerability

“…27 Another study in human retinal pigment epithelium found that overexpression of CD97 activates MAPK signaling, as measured by increased serum response element (SRE)-driven luciferase expression in a luciferase-reporter system. 78 Interestingly, we did not observe this finding using an SRE-driven luciferase assay in our PDGCs, nor did we detect any other G protein-coupling of CD97 in GBM cells using other luciferase-driven reporter systems ( Supp. Fig.…”

The expression profile and tumorigenic mechanisms of CD97 (ADGRE5) in glioblastoma render it a targetable vulnerability

“… 27 Another study in human retinal pigment epithelium found that overexpression of CD97 activates MAPK signaling, as measured by increased serum response element (SRE)-driven luciferase expression in a luciferase reporter system. 79 Interestingly, we did not observe this finding using an SRE-driven luciferase assay in our PDGCs, nor did we detect any other G protein coupling of CD97 in GBM cells using other luciferase-driven reporter systems ( Figure S4B ). We previously found that CD97 activated both MAPK and AKT signaling in leukemic stem cells.…”

Single‐cell analysis revealed a potential role of T‐cell exhaustion in colorectal cancer with liver metastasis

“…ADGRE5 (CD97) has been considered as the most promising target of adhesion G protein‐coupled receptors in glioblastoma 44 . ADGRE5 in retinal pigment epithelial cells also controls leukocyte activation and trafficking in uveal retinal inflammation 45 . CD55, a complement regulatory protein, binds to multiple ligands that are constitutively expressed on monocytes or granulocytes and is rapidly upregulated during activation of T cells 46 .…”

“… 44 ADGRE5 in retinal pigment epithelial cells also controls leukocyte activation and trafficking in uveal retinal inflammation. 45 CD55, a complement regulatory protein, binds to multiple ligands that are constitutively expressed on monocytes or granulocytes and is rapidly upregulated during activation of T cells. 46 It has been shown that CD55 regulates both innate and adaptive immune responses and mediates T‐cell co‐stimulation when binding to CD97.…”