Biliverdin reductase: PKC interaction at the cross-talk of MAPK and PI3K signaling pathways

Biliverdin reductase (BVR) was characterized some 25 years ago as a unique dual-cofactor/pH-dependent enzyme that catalyzes the reduction of biliverdin-IXa. Our knowledge of functions of BVR has increased enormously in recent years. hBVR functions in the IR/IGF-1-controlled regulation of the MAPK and PI3K cascades that are linked by the PKC enzymes. The first of the two culminates in the activation of transcription factors for oxidative stress-responsive genes, including ho-1, where BVR functions as both a bZip (basic leucine zipper) transcription factor and a kinase. The second pathway amplifies the insulin/growth-factor signal for protein/DNA synthesis and glucose transport downstream of PI3K. hBVR is a transactivator of PKC-betaII, and thus an integral component of the "activation loop" linking MAPK, PKC-betaII, and PI3K to insulin/growth-factor signaling. The emergence of biliverdin and bilirubin as a newly defined category of modulators of cell signaling and kinase activity further underscores the critical input of hBVR in the response of intracellular pathways into the external environment. Structural features of BVR and recent findings relevant to its function in cell-signaling pathways are reviewed here and are intended to complement a recent commentary on the role of BVR in linking heme metabolism and cell signaling.