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J. Biol. Chem., Vol. 282, Issue 11, 8110-8122, March 16, 2007

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Human Biliverdin Reductase, a Previously Unknown Activator of Protein Kinase C II^*

From the Department of Biochemistry and Biophysics, University of Rochester School of Medicine, Rochester, New York 14624

Human biliverdin reductase (hBVR), a dual specificity kinase (Ser/Thr/Tyr) is, as protein kinase C (PKC) II, activated by insulin and free radicals (Miralem, T., Hu, Z., Torno, M. D., Lelli, K. M., and Maines, M. D. (2005) J. Biol. Chem. 280, 17084–17092; Lerner-Marmarosh, N., Shen, J., Torno, M. D., Kravets, A., Hu, Z., and Maines, M. D. (2005) Proc. Natl. Acad. Sci. U. S. A. 102, 7109–7114). Here, by using 293A cells co-transfected with pcDNA3-hBVR and PKC II plasmids, we report the co-immunoprecipitation of the proteins and co-purification in the glutathione S-transferase (GST) pulldown assay. hBVR and PKC II, but not the reductase and PKC , transphosphorylated in assay systems supportive of activity of only one of the kinases. PKC II K371R mutant protein ("kinase-dead") was also a substrate for hBVR. The reductase increased the V_max but not the apparent K_m values of PKC II for myelin basic protein; activation was independent of phospholipids and extended to the phosphorylation of S2, a PKC-specific substrate. The increase in substrate phosphorylation was blocked by specific inhibitors of conventional PKCs and attenuated by sihBVR. The effect of the latter could be rescued by subsequent overexpression of hBVR. To a large extent, the activation was a function of the hBVR N-terminal chain of valines and intact ATP-binding site and the cysteine-rich C-terminal segment. The cobalt protoporphyrin-activated hBVR phosphorylated a threonine in a peptide corresponding to the Thr⁵⁰⁰ in the human PKC II activation loop. Neither serine nor threonine residues in peptides corresponding to other phosphorylation sites of the PKC II nor PKC activation loop-derived peptides were substrates. The phosphorylation of Thr⁵⁰⁰ was confirmed by immunoblotting of hBVR·PKC II immunocomplex. The potential biological relevance of the hBVR activation of PKC II was suggested by the finding that in cells transfected with the PKC II, hBVR augmented phorbol myristate acetate-mediated c-fos expression, and infection with sihBVR attenuated the response. Also, in cells overexpressing hBVR and PKC II, as well as in untransfected cells, upon treatment with phorbol myristate acetate, the PKC translocated to the plasma membrane and co-localized with hBVR. hBVR activation of PKC II underscores its potential function in propagation of signals relayed through PKCs.

Received for publication, December 16, 2005 , and in revised form, November 20, 2006.

^* This work was supported by Grants ES12187 and ES004066 from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

² Both authors contributed equally to this work.

¹ To whom correspondence should be addressed. Tel.: 585-275-5383; Fax: 585-275-6007; E-mail: mahin_maines{at}urmc.rochester.edu.

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