Interaction of human biliverdin reductase with Akt/protein kinase B and phosphatidylinositol‐dependent kinase 1 regulates glycogen synthase kinase 3 activity: a novel mechanism of Akt activation

Abstract

Biliverdin reductase A (BVR) and Akt isozymes have overlapping pleiotropic functions in the insulin/PI3K/MAPK pathway. Human BVR (hBVR) also reduces the hemeoxygenase activity product biliverdin to bilirubin and is directly activated by insulin receptor kinase (IRK). Akt isoenzymes (Akt1-3) are downstream of IRK and are activated by phosphatidylinositol-dependent kinase 1 (PDK1) phosphorylating T(308) before S(473) autophosphorylation. Akt (RxRxxSF) and PDK1 (RFxFPxFS) binding motifs are present in hBVR. Phosphorylation of glycogen synthase kinase 3 (GSK3) isoforms α/β by Akts inhibits their activity; nonphosphorylated GSK3β inhibits activation of various genes. We examined the role of hBVR in PDK1/Akt1/GSK3 signaling and Akt1 in hBVR phosphorylation. hBVR activates phosphorylation of Akt1 at S(473) independent of hBVR's kinase competency. hBVR and Akt1 coimmunoprecipitated, and in-cell Förster resonance energy transfer (FRET) and glutathione S-transferase pulldown analyses identified Akt1 pleckstrin homology domain as the interactive domain. hBVR activates phosphorylation of Akt1 at S(473) independent of hBVR's kinase competency. Site-directed mutagenesis, mass spectrometry, and kinetic analyses identified S(230) in hBVR (225)RNRYLSF sequence as the Akt1 target. Underlined amino acids are the essential residues of the signaling motifs. In cells, hBVR-activated Akt1 increased both GSK3α/β and forkhead box of the O class transcription class 3 (FoxO3) phosphorylation and inhibited total GSK3 activity; depletion of hBVR released inhibition and stimulated glucose uptake. Immunoprecipitation analysis showed that PDK1 and hBVR interact through hBVR's PDK1 binding (161)RFGFPAFS motif and formation of the PDK1/hBVR/Akt1 complex. sihBVR blocked complex formation. Findings identify hBVR as a previously unknown coactivator of Akt1 and as a key mediator of Akt1/GSK3 pathway, as well as define a key role for hBVR in Akt1 activation by PDK1.-Miralem, T., Lerner-Marmarosh, N., Gibbs, P. E. M., Jenkins, J. L., Heimiller, C., Maines, M. D. Interaction of human biliverdin reductase with Akt/protein kinase B and phosphatidylinositol-dependent kinase 1 regulates glycogen synthase kinase 3 activity: a novel mechanism of Akt activation.

Biliverdin Reductase A (BVRA) Knockout in Adipocytes Induces Hypertrophy and Reduces Mitochondria in White Fat of Obese Mice

“…One of the primary regulators of AKT activity and insulin signaling is BVRA [18,57]. Studies by Miralem et al elegantly demonstrated that BVRA modulates AKT activity by aiding the formation of a complex with phosphatidylinositol-dependent kinase 1 (PDK1) [12]. The interaction of BVRA with AKT increases activity and phosphorylation (pAKT), improving insulin sensitivity [12,21].…”

“…Studies by Miralem et al elegantly demonstrated that BVRA modulates AKT activity by aiding the formation of a complex with phosphatidylinositol-dependent kinase 1 (PDK1) [12]. The interaction of BVRA with AKT increases activity and phosphorylation (pAKT), improving insulin sensitivity [12,21]. Specific peptide sequences within the BVRA protein itself can impact insulin sensitivity through activation or inhibition of the insulin receptor kinase (IRK) domain [58].…”

BVR-A Deficiency Leads to Autophagy Impairment through the Dysregulation of AMPK/mTOR Axis in the Brain—Implications for Neurodegeneration

“…BVR-A was shown to be a Ser/Thr/Tyr kinase able to regulate a number of pathways involved in cell growth, differentiation and survival [1,3,12]. In particular, BVR-A was identified as a novel regulator of the insulin/IGF1 signaling in vitro [13][14][15] and recent studies showing that loss of BVR-A impairs insulin signaling activation and cell metabolism also in vivo support this hypothesis [16][17][18][19].…”

Biological signaling by carbon monoxide and carbon monoxide-releasing molecules

“…In contrast, iron exerts pro-oxidant effects and following its release, cells respond by increasing the expression of the iron storage protein ferritin (8). For the scope of this review we will focus on CO, although biliverdin and bilirubin also possess interesting signaling transduction activities that are being investigated (11,37,64) and may prove to be as relevant as those of CO to explain the beneficial role of HO-1. In general, induction of HO-1 is correlated with protection of organs and tissues after injury.…”