The role of the RGD motif in CD97/ADGRE5-and EMR2/ADGRE2-modulated tumor angiogenesis

• Published in: Biochemical and biophysical research communications Vol. 520; no. 2; pp. 243 - 249
• Main Authors: Tjong, Wen-Ye, Lin, Hsi-Hsien
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 03.12.2019
• Subjects: Adhesion GPCR; Angiogenesis; Matrix metalloproteinase; N-cadherin; RGD motif; RGD motif; Angiogenesis; Adhesion GPCR; Matrix metalloproteinase; N-cadherin
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2019.09.113

CD97/ADGRE5, an adhesion G protein-coupled receptor (aGPCR), is highly expressed in several tumor cell types. CD97 has been shown to modulate tumorigenesis in part by promoting HUVEC migration, invasion and angiogenesis through the interaction with integrin α5β1 via its ectodomain RGD motif. In this study, we show that CD97 could induce angiogenesis via an alternative RGD-independent mechanism. Overexpression of CD97 with the wild-type or mutant RGD motif in HT1080 cells led to up-regulated MMP-9 and induced angiogenesis as revealed by the in vitro endothelial cell tube formation assay and in ovo chick chorioallantoic membrane assay. By contrast, expression of EMR2/ADGRE2, the CD97-homologous aGPCR that contains a corresponding SGD sequence, fails to induce angiogenesis due to lower MMP-9 expression. Interestingly, a single change of the SGD to RGD sequence allowed EMR2 to up-regulate MMP-9 expression, leading to enhanced angiogenesis. MMP-9 was shown to promote the proliferation, migration, and invasion of HUVEC partly by modulating the levels of VEGF, PIGF, and bFGF. Finally, we showed that the MMP-9 expression was in turn modulated by N-cadherin that was up-regulated by CD97 and EMR2/RGD. Our results indicate that two homologous aGPCRs, CD97 and EMR2, modulate angiogenesis and HUVEC proliferation, migration, and invasion through N-cadherin-regulated MMP-9 expression by RGD-independent and -dependent mechanisms, respectively. [Display omitted] •CD97 stimulates angiogenesis through RGD-independent mechanism, while EMR2 via RGD-dependent mechanism.•CD97 and EMR2-RGD promote angiogenesis by overexpressing MMP-9.•MMP-9 upregulates the mRNA and protein levels of VEGF, PIGF, and bFGF.•MMP-9 expression is in turn modulated by N-cadherin upregulated by CD97 expression.