RING-finger E3 ligases regulatory network in PI3K/AKT-mediated glucose metabolism

Abstract

The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway plays an essential role in glucose metabolism, promoting glycolysis and resisting gluconeogenesis. PI3K/AKT signaling can directly alter glucose metabolism by phosphorylating several metabolic enzymes or regulators of nutrient transport. It can indirectly promote sustained aerobic glycolysis by increasing glucose transporters and glycolytic enzymes, which are mediated by downstream transcription factors. E3 ubiquitin ligase RING-finger proteins are mediators of protein post-translational modifications and include the cullin-RING ligase complexes, the tumor necrosis factor receptor-associated family, the tripartite motif family and etc. Some members of the RING family play critical roles in regulating cell signaling and are involved in the development and progression of various metabolic diseases, such as cancer, diabetes, and dyslipidemia. And with the progression of modern research, as a negative or active regulator, the RING-finger adaptor has been found to play an indispensable role in PI3K/AKT signaling. However, no reviews have comprehensively clarified the role of RING-finger E3 ligases in PI3K/AKT-mediated glucose metabolism. Therefore, in this review, we focus on the regulation and function of RING ligases in PI3K/AKT-mediated glucose metabolism to establish new insights into the prevention and treatment of metabolic diseases.

Targeting PI3K/AKT signaling pathway in obesity

“…Downstream signals of PI3K are mediated by multiple serine/threonine (Ser/Thr) kinases, including phosphoinositide-dependent protein kinase 1 (PDK1), AKT, mammalian target of rapamycin complex (mTORC), protein kinase C (PKC), ribosomal protein S6 kinase (S6K), AKT substrate of 160 kDa (AS160) and glycogen synthase kinase 3 (GSK3), which regulate the activity of various transcriptional factors, such as Forkhead box protein O1 (FOXO1), peroxisome proliferator-activated receptors (PPARs), PPARγ coactivator-1 alpha (PGC1α), and sterol regulatory element-binding proteins (SREBPs). These promote the metabolic actions of insulin on glucose, lipid, and mitochondrial metabolism, as well as effects on cell proliferation, differentiation, growth and apoptosis [30][31][32][33][34][35][36][37].…”

“…Another concern is that PI3K/AKT signaling mediates a wide spectrum of processes in the whole organism (special attention should be paid to oncogenesis), which additionally complicates development of an anti-obesity therapy that specifically targets at its modulation [26,33,36]. Finally, selective interaction with tissue specific isoforms of both PI3K and AKT could probably ensure tissue specific response [140].…”

ARID3A plays a key regulatory role in palmitic acid‐stimulated milk fat synthesis in mouse mammary epithelial cells

“…We showed that ARID3A In our study, we found that PI3K inhibition blocked the stimulatory effect of PA on ARID3A protein expression. The PI3K signaling is one of the most important intracellular signaling sensing nutrients to regulate multiple cellular functions, including cell proliferation, differentiation, and expression of many genes (Tsalikis et al, 2013;Wang et al, 2022). Fatty acids can promote milk fat synthesis in mammary epithelial cells through the PI3K signaling (Jin et al, 2022;F.…”

An insight into PI3k/Akt pathway and associated protein–protein interactions in metabolic syndrome: A recent update

“…Cellular signaling pathways are an intricate ballet of interacting proteins involved in transmitting signals from extracellular to intracellular regions 7,8 . Notably, emerging research has markedly improved our understanding of PI3K/Akt‐associated signaling pathways in MS 9–12 . Cellular receptors, secondary molecules/messengers, and transcriptional factors are imperative elements for signaling pathways 8 .…”