hBVR and Protein Kinases & Phosphatases
Cell signaling activities are controlled through phosphorylation by kinases that most often results in activation, and dephosphorylation by phosphatases that lead to inactivation of substrates. We have focused on kinases, in particular PKCs and ERK1/2, with linked activities. The PKC family of signaling proteins functions at the intersection of a wide variety of signal transduction pathways, the kinases are therefore considered as key regulators of responses to extracellular stimuli. The PKC family consists of three subgroups, i.e., the conventional, novel and atypical PKCs (cPKC, nPKC, aPKC, respectively), which are characterized by differences in protein structure, mechanism of activation and function. Previously, we had demonstrated regulation of members of cPKCs, PKCβ11 and aPKCs, PKCζ by hBVR (JBC 282, 8110, 2007; FASEB J. 21, 3949, 2007). Recently we focused on PKCδ, a member of nPKCs (JBC 287, 1066, 2012; JBC 287, 24698, 2012).
As depicted in the above figure, a remarkable spectrum of events ensues as the result of PKCδ and hBVR interaction. We have found that the increased activity of PKCδ is dependent on formation of a complex with hBVR. A direct evidence for association of the proteins was provided by an in vivo assay, using FRET-FLIM and IGF-1-treated cells. The recent study (JBC 287, 24698, 2012) also revealed an unexpected regulatory interplay between PKCδ and hBVR in modulating cell death/survival in response to various activating stimuli. PKCδ is a Ser/Thr kinase and its activation is linked to signaling pathways that govern cell growth, survival and death. In addition to its role in cell growth and apoptotic processes, PKCδ has been implicated in regulation of membrane ion channels, activation of transcriptional factors, antigen presentation and with various cancers. hBVR, a Ser/Thr/Tyr kinase and a reductase is a 296 residue soluble polypeptide with an extensive range of input into signal transduction pathways, as well as being a key component of cellular defense mechanisms; the reductase activity of hBVR is directly associated with its phosphorylation state. Depending on the type of stimulus and cell type, activation of PKCδ and hBVR can exert opposing effects on apoptotic events or bring about a similar outcome on cell survival.
A central role for hBVR in PKCδ/ERK-mediated signal transduction was proposed based on hBVR serving as a scaffold/bridge in the formation of a ternary complex that contained hBVR, ERK, and PKCδ. PKCδ is known to function in the ERK1/2 signaling pathway, and is believed to directly activate the ERK proteins. In addition, hBVR is essential for activation of ERK 1/2 by MEK 1 (Prac. Nat. Acad. Sci. 105, 6870, 2008), also by functioning as a scaffold/bridge for placing ERK in proximity of MEK1. The ERK proteins are of fundamental importance in the regulation of cell proliferation and differentiation, and of the stress responses ERK1/2 is known to activate some 50 transcription factors, including Elk and NF-κB. hBVR was also found to be essential for the nuclear import and export of ERK. Formation of the ternary complex was required for downstream nuclear signaling mediated by ERK2. The substrate for hBVR is also an active player in cell signaling. Biliverdin non-covalently inhibits PKCδ; whereas PKCδ potentiates hBVR reductase activity and accelerates the rate of bilirubin formation.
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