Research Topics

Insulin signaling and ER

Despite the fact that X-box binding protein-1 (XBP-1) is one of the main regulators of the unfolded protein response (UPR), the modulators of XBP-1 are poorly understood. We showed that the regulatory subunits of phosphotidyl inositol 3-kinase (PI3K), p85alpha (encoded by Pik3r1) and p85beta (encoded by Pik3r2) form heterodimers that are disrupted by insulin treatment. This disruption of heterodimerization allows the resulting monomers of p85 to interact with, and increase the nuclear translocation of, the spliced form of XBP-1 (XBP-1s). The interaction between p85 and XBP-1s is lost in ob/ob mice, resulting in a severe defect in XBP-1s translocation to the nucleus and thus in the resolution of endoplasmic reticulum (ER) stress. These defects are ameliorated when p85s are overexpressed in the liver of ob/ob mice.

BRD7 and ER homeostasis

Bromodomain-containing protein 7 (BRD7) is a member of the bromodomain-containing protein family that is known to play a role as tumor suppressors. We showed that BRD7 is a component of the unfolded protein response (UPR) signaling through its ability to regulate X-box binding protein 1 (XBP1) nuclear translocation. BRD7 interacts with the regulatory subunits of phosphatidylinositol 3-kinase (PI3K) and increases the nuclear translocation of both p85a and p85b and the spliced form of XBP1 (XBP1s). Deficiency of BRD7 blocks the nuclear translocation of XBP1s. Furthermore, our in vivo studies have shown that BRD7 protein levels are reduced in the liver of obese mice, and reinstating BRD7 levels in the liver restores XBP1s nuclear translocation, improves glucose homeostasis, and ultimately reduces the blood glucose levels in the obese and diabetic mouse models.

BRD7 and glucose homeostasis

Insulin activates insulin receptor, which recruits and phosphorylates its substrate adaptor proteins, such as the insulin receptor substrate (IRS) family proteins. Activated IRS proteins are recognized by the regulatory subunits of phosphatidylinositol 3-kinase (PI3K), p85alpha an p85beta. p85 is required for the stability of the catalytic subunits of PI3K, p110, and mediates the recruitment of p110 subunits to upstream activators. PI3K leads to activation of effector proteins, such as Akt. However, when p85 regulatory subunits are in excess of p110 catalytic subunits, p85s form homodimers that compete with p85-p110 heterodimers for binding to upstream activators of PI3K (e.g., IRS1) and impair insulin-induced PI3K signaling (Figure 1A) [47]. BRD7 regulates several major nodes in the insulin signaling pathway. BRD7 competes with p110 for binding to p85. BRD7 binds to the subset of p85 proteins that are not bound to p110, and transports these free p85 monomers to the nucleus, thereby increases insulin signaling (Figure A). However, in cells or tissues where the ratio of p85 to p110 is approximately 1:1, BRD7 upregulation decreases PI3K signaling by preventing p85 from binding to p110 (Figure B).

BRD7 and GSK3beta

BRD7 increases phosphorylation of glycogen synthase kinase 3β (GSK3β) in response to activation of the insulin receptor-signaling pathway shortly after insulin stimulation and the nutrient-sensing pathway after feeding. BRD7 mediates phosphorylation of GSK3β at the Serine 9 residue and this effect on GSK3β occurs even in the absence of AKT activity.

BRD7 mediates phosphorylation of ribosomal protein S6 kinase (S6K) and leads to increased phosphorylation of the eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and, therefore, relieves its inhibition of the eukaryotic translation initiation factor 4E (eIF4E). The increase in phosphorylation of 4E-BP1 with BRD7 overexpression is blunted in the absence of AKT activity.

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