The regulatory subunits of PI3K, p85α and p85β, differentially affect BRD7-mediated regulation of insulin signaling

Abstract

Bromodomain-containing protein 7 (BRD7) has been shown to interact with the regulatory subunit of phosphatidylinositol 3-kinase (PI3K), p85, in the insulin signaling pathway. Here, we show that upregulation of hepatic BRD7 improves glucose homeostasis even in the absence of either p85 isoform, p85α or p85β. However, BRD7 leads to differential activation of downstream effector proteins in the insulin signaling pathway depending on which isoform of p85 is present. In the presence of only p85α, BRD7 overexpression increases phosphorylation of insulin receptor upon insulin stimulation, without increasing the recruitment of p85 to insulin receptor substrate. Overexpression of BRD7 also increases activation of Akt in response to insulin but does not affect basal phosphorylation levels of Akt. Meanwhile, the phosphorylation of glycogen synthase kinase 3β (GSK3β) is increased by overexpression of BRD7. On the other hand, in the presence of only p85β, BRD7 overexpression does not affect phosphorylation levels of insulin receptor, and Akt phosphorylation is not affected by insulin stimulation following BRD7 upregulation. However, BRD7 overexpression leads to increased basal phosphorylation levels of Akt and GSK3β. These data demonstrate that BRD7’s action on glucose homeostasis does not require the presence of both p85 isoforms, and p85α and p85β have unique roles in insulin signaling in the liver.

Divergent roles of the regulatory subunits of class IA PI3K

“…In mice with deletion of p85β, overexpression of BRD7 in the liver during high-fat diet challenge does not affect the phosphorylation of Akt at the basal state without any stimulation. However, in mice with a lack of hepatic p85α, the upregulation of BRD7 leads to increased Akt phosphorylation under the same conditions ( 83 ). On the other hand, the upregulation of BRD7 leads to an increase in Akt phosphorylation upon insulin stimulation in the liver of high-fat diet-induced obese p85β knockout mice ( 83 ).…”

“…However, in mice with a lack of hepatic p85α, the upregulation of BRD7 leads to increased Akt phosphorylation under the same conditions ( 83 ). On the other hand, the upregulation of BRD7 leads to an increase in Akt phosphorylation upon insulin stimulation in the liver of high-fat diet-induced obese p85β knockout mice ( 83 ). However, in high-fat diet fed hepatic p85α knockout mice, the effect of BRD7 on Akt phosphorylation in response to insulin stimulation is abolished ( 83 ).…”

“…On the other hand, the upregulation of BRD7 leads to an increase in Akt phosphorylation upon insulin stimulation in the liver of high-fat diet-induced obese p85β knockout mice ( 83 ). However, in high-fat diet fed hepatic p85α knockout mice, the effect of BRD7 on Akt phosphorylation in response to insulin stimulation is abolished ( 83 ). These observations indicate that p85α plays a role in mediating the effect of BRD7 on Akt phosphorylation in response to insulin, while p85β is involved in the regulation during the basal state without responding to external stimuli.…”

“…In the liver of obese mice, the upregulation of BRD7 promotes the interaction between BRD7 and p85, leading to increased nuclear translocation of p85. This balances the p85-p110 ratio, thereby improves PI3K signaling, resulting in enhanced Akt phosphorylation at threonine 308 and serine 473 residues ( 82 , 83 ). Conversely, in the HeLa cervical cancer cell line, the sequestration of p85 in the nucleus by overexpression of BRD7 reduces PI3K activity, and leading to decreased Akt phosphorylation.…”

“…This activation occurs independently of p85’s role in the PI3K complex under specific stimuli, such as insulin and tunicamycin. It was shown that the N terminus and SH2 domains of p85α are required for the activation of JNK by CDC42 and MKK4 (mitogen-activated protein kinase-kinase 4), highlighting the communication between the PI3K pathway and cellular stress responses ( 83 ).…”