Abstract
The expanse of human biliverdin reductase (hBVR) functions in the cells is arguably unmatched by any single protein. hBVR is a Ser/Thr/Tyr-kinase, a scaffold protein, a transcription factor, and an intracellular transporter of gene regulators. hBVR is an upstream activator of the insulin/IGF-1 signaling pathway and of protein kinase C (PKC) kinases in the two major arms of the pathway. In addition, it is the sole means for generating the antioxidant bilirubin-IXα. hBVR is essential for activation of ERK1/2 kinases by upstream MAPKK-MEK and by PKCδ, as well as the nuclear import and export of ERK1/2. Small fragments of hBVR are potent activators and inhibitors of the ERK kinases and PKCs: as such, they suggest the potential application of BVR-based technology in therapeutic settings. Presently, we have reviewed the function of hBVR in cell signaling with an emphasis on regulation of PKCδ activity.
Highlights
STRUCTURE OF HUMAN BILIVERDIN REDUCTASE AND ITS FUNCTIONS IN CELL SIGNALING PATHWAYS Biliverdin reductase (BVR), purified to homogeneity from rat liver, was characterized as an enzyme that was capable of reducing biliverdin-IXα to bilirubin-IXα and was shown to exhibit a unique, dual cofactor/pH optimum profile (Kutty and Maines, 1981)
Since human BVR (hBVR) has been observed to provide cytoprotective functions during oxidative stress (Miralem et al, 2005), it is possible that the association of hBVR, PKCδ and extracellular receptor kinase 1/2 (ERK1/2) in a ternary complex may provide a mechanism to protect the protein kinase C (PKC) from cleavage to its constitutively active, pro-apoptotic form, thereby favoring those functions involved in cell survival
Because the www.frontiersin.org hBVR regulation of PKC signaling hBVR/PKCδ/ERK2 complex is critical for downstream signaling by ERK2, the finding that treatment with peptides disrupts complex formation in the cell and leads to inhibition of ERK-dependent activation of Elk-mediated gene expression offers a novel approach to regulation of ERK signaling
Summary
STRUCTURE OF HUMAN BILIVERDIN REDUCTASE AND ITS FUNCTIONS IN CELL SIGNALING PATHWAYS Biliverdin reductase (BVR), purified to homogeneity from rat liver, was characterized as an enzyme that was capable of reducing biliverdin-IXα to bilirubin-IXα and was shown to exhibit a unique, dual cofactor/pH optimum profile (Kutty and Maines, 1981). Mutations in the 162FGFPAF sequence, that resembles the high affinity C-Box binding motif found in ERK1/2 associated proteins (Jacobs et al, 1999) and in the low affinity 275KKRILHCLGL D-Box-like sequence (Minden and Karin, 1997) prevented formation of the complex, and attenuated ERK activation and signaling in response to IGF-1.
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