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BIOCHEMISTRY
Human biliverdin reductase is an ERK activator; hBVR is an ERK nuclear transporter and is required for MAPK signaling

Nicole Lerner-Marmarosh, Tihomir Miralem, Peter E. M. Gibbs, and Mahin D. Maines^*

University of Rochester School of Medicine, Department of Biochemistry and Biophysics, Rochester, NY 14642

Edited by Fred Sherman, University of Rochester Medical Center, Rochester, NY, and approved March 15, 2008 (received for review January 29, 2008)

Abstract

Activation of the MEK/ERK/Elk-signaling cascade is a mechanism for relaying mitogenic and stress stimuli for gene activation. MEK1 is the proximate kinase for activation of ERK1/2, and nuclear targeting of ERK1/2 is obligatory for Elk1 transcriptional activity. Human biliverdin reductase (hBVR) is a recently described Ser/Thr/Tyr kinase in the MAPK insulin/insulin-like growth factor 1 (IGF1)-signaling cascade. Using 293A cells and in vitro experiments, we detail the formation of a ternary complex of MEK/ERK/hBVR, activation of MEK1 and ERK1/2 kinase activities by hBVR, and phosphorylation of hBVR by ERK1/2. hBVR is nearly as effective as IGF1 in activating ERK; intact hBVR ATP-binding domain is necessary for Elk1 activation, whereas protein–protein interaction is the basis for hBVR activation of MEK1 and ERK. The two MAPK docking consensus sequences present in hBVR, F¹⁶²GFP and K²⁷⁵KRILHCLGL (C- and D-box, respectively), are ERK interactive sites; interaction at each site is critical for ERK/Elk1 activation. Transfection with mutant hBVR-P¹⁶⁵ or peptides corresponding to the C- or D-box blocked activation of ERK by IGF1. Transfection with D-box mutant hBVR prevented the activation of ERK by wild-type protein and dramatically decreased Elk1 transcriptional activity. hBVR is a nuclear transporter of ERK; experiments with hBVR nuclear export signal (NES) and nuclear localization signal (NLS) mutants demonstrated its critical role in the nuclear localization of IGF-stimulated ERK for Elk1 activation. These findings, together with observations that si-hBVR blocked activation of ERK and Elk1 by IGF1 and prevented formation of ternary complex between MEK/ERK/hBVR, define the critical role of hBVR in ERK signaling and nuclear functions of the kinase.

Elk-1 | ERK docking sites | ERK MAP kinase | heme oxygenase-1 | adapter/scaffold proteins

Author contributions: M.D.M. designed research; N.L.-M. and T.M. performed research; P.E.M.G. contributed new reagents/analytic tools; N.L.-M., T.M., and M.D.M. analyzed data; and N.L.-M., T.M., P.E.M.G., and M.D.M. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

*To whom correspondence should be addressed. E-mail: mahin_maines{at}urmc.rochester.edu

© 2008 by The National Academy of Sciences of the USA

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