Identification of Serine 348 on the Apelin Receptor as a Novel Regulatory Phosphorylation Site in Apelin-13-induced G Protein-independent Biased Signaling

Abstract

Background: Apelin and apelin receptor (APJ)-induced G␣ i activation evokes a protective response in cardiac hypertrophy, whereas G-protein-independent signaling induces hypertrophy. Results: Serine 348 is identified as one phosphorylation site in APJ, which is crucial for APJ interactions with GRK2/5, ␤-arrestin1/2, and its internalization. Conclusion: Mutation at serine 348 modulates G-independent signaling of APJ. Significance: Understanding APJ signaling and regulation could provide novel clues for the development of functionally selective APJ ligands.

Apelin receptors: From signaling to antidiabetic strategy

“…The murine apelin receptor is preferentially coupled to G αi1 , G αi2 but not G αi3 in Chinese Hamster Ovary cells through which apelin induces ERKs and Akt activation and inhibits adenylyl cyclase . Likewise, the same results were obtained in HEK293 cells expressing the human APJ receptor which activates G αi2 (Bai et al, 2008;Chen et al, 2014). However, depending on the cell type studied, apelin receptor can be associated with other G proteins.…”

“…Indeed, Chen et al (2014) clearly demonstrated that the phosphorylation of Ser 348 on APJ was not necessary for G protein activation induced by apelin-13 but instead was crucial for G protein-coupled receptor kinases and β-arrestin recruitment, APJ internalization and ERKs activation.…”

“…Indeed, they can bind various intracellular partners under different pathophysiological conditions, thus organizing multi-protein signaling complexes and localizing them to distinct subcellular compartments (Gurevich and Gurevich, 2014;Kang et al, 2014). Regarding apelin signaling, two recent studies demonstrated that both apelin-13 and apelin-17 can stimulate ERKs phosphorylation in a G-protein and β-arrestin dependent manner (Ceraudo et al, 2014;Chen et al, 2014). However, despite the activation of ERK as a common intracellular effector, these two signaling pathways would not be involved in the same physiological effects.…”

Apelin receptor homodimer-oligomers revealed by single-molecule imaging and novel G protein-dependent signaling

“…Cells expressing Gα-Rluc8 and APJ-Venus served as a positive control, and two negative controls (Gα-Rluc8 and APJ-VN173, Gα-Rluc8 and APJ-VC155A) were also introduced. These tags have been characterized and do not significantly alter the function of the wildtype APJ22 (Fig. S5).…”

Temporal Expression of Apelin/Apelin Receptor in Ischemic Stroke and its Therapeutic Potential

“…Hypoxia promotes both apelin and APLNR expression accompanying with HIF-1α induction, suggesting that upregulation of APLNR may be mediated by both apelin and/or HIF-1α (He et al, 2015). Moreover, APLNR undergoes multiple post-translational modifications, including glycosylation, phosphorylation and palmitoylation, which may contribute to the alteration of APLNR at the protein level by affecting its turnover rate (Figure 1; O’Carroll et al, 2013; Chen et al, 2014). For example, the phosphorylation status of regulator of calcineurin 1(RCAN1) has a significant effect on its degradation rate (Genescà et al, 2003).…”