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Biliverdin reductase: more than a namesake - the reductase, its Peptide fragments, and biliverdin regulate activity of the three classes of protein kinase C.

Gibbs PE, Tudor C, Maines MD - Front Pharmacol (2012)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry Rochester, NY, USA.

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.

No MeSH data available.


Related in: MedlinePlus

Structural domains of protein kinase C. The three classes of PKCs are shown. Members of each class have a catalytic domain that encompasses the C-terminus of the protein (shown in orange). Positions of residues in the catalytic domain that are phosphorylated during activation of the kinases are shown as yellow circles above each map. The threonine residue in the activation loop is the first to be phosphorylated, which allows phosphorylation of the threonine/serine in the turn motif and the serine/threonine in the hydrophobic motif, resulting in full activity of the kinase. There is no phosphorylation target in the atypical kinase hydrophobic motif; negative charge is supplied by the glutamic acid residue (indicated by the brown circle). The regulatory domains are located in the N-terminal half, and consist of C1 (blue), C2 (red) and pseudosubstrate domains (green). The positions of the C1 and C2 domains of conventional PKCs are reversed in the novel PKCs. Atypical PKCs lack a C2 domain, and have only a partial C1 domain. Redrawn from Steinberg (2008), Newton (2010).
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Figure 2: Structural domains of protein kinase C. The three classes of PKCs are shown. Members of each class have a catalytic domain that encompasses the C-terminus of the protein (shown in orange). Positions of residues in the catalytic domain that are phosphorylated during activation of the kinases are shown as yellow circles above each map. The threonine residue in the activation loop is the first to be phosphorylated, which allows phosphorylation of the threonine/serine in the turn motif and the serine/threonine in the hydrophobic motif, resulting in full activity of the kinase. There is no phosphorylation target in the atypical kinase hydrophobic motif; negative charge is supplied by the glutamic acid residue (indicated by the brown circle). The regulatory domains are located in the N-terminal half, and consist of C1 (blue), C2 (red) and pseudosubstrate domains (green). The positions of the C1 and C2 domains of conventional PKCs are reversed in the novel PKCs. Atypical PKCs lack a C2 domain, and have only a partial C1 domain. Redrawn from Steinberg (2008), Newton (2010).

Mentions: The cPKCs, nPKCs, and aPKCs have homologous catalytic kinase domains that encompass the C-terminal half of the molecules (Figure 2; Steinberg, 2008; Newton, 2010). The primary structure of this domain is well conserved between the proteins, and it includes essential sequence motifs that are common to all members as well as being required for maturation of the kinase. These motifs include the activation loop, which contains a threonine residue that generally must be phosphorylated for catalytic activity; in the case of PKCδ, phosphorylation of this site is observed, but it is not essential. Phosphorylation of the activation loop threonine is otherwise the essential first step in maturation of the newly synthesized protein. All members have both a turn motif and a C-terminal hydrophobic motif; each motif contains serine or threonine targets for autophosphorylation, a requirement for full maturation of the enzyme. One exception is noted for the atypical kinases, which have glutamic acid, an amino acid known to mimic phosphoSer/Thr, at the hydrophobic motif phosphoacceptor site. Phosphate incorporated during the maturation process remains an integral part of the protein, with little or no turnover.


Biliverdin reductase: more than a namesake - the reductase, its Peptide fragments, and biliverdin regulate activity of the three classes of protein kinase C.

Gibbs PE, Tudor C, Maines MD - Front Pharmacol (2012)

Structural domains of protein kinase C. The three classes of PKCs are shown. Members of each class have a catalytic domain that encompasses the C-terminus of the protein (shown in orange). Positions of residues in the catalytic domain that are phosphorylated during activation of the kinases are shown as yellow circles above each map. The threonine residue in the activation loop is the first to be phosphorylated, which allows phosphorylation of the threonine/serine in the turn motif and the serine/threonine in the hydrophobic motif, resulting in full activity of the kinase. There is no phosphorylation target in the atypical kinase hydrophobic motif; negative charge is supplied by the glutamic acid residue (indicated by the brown circle). The regulatory domains are located in the N-terminal half, and consist of C1 (blue), C2 (red) and pseudosubstrate domains (green). The positions of the C1 and C2 domains of conventional PKCs are reversed in the novel PKCs. Atypical PKCs lack a C2 domain, and have only a partial C1 domain. Redrawn from Steinberg (2008), Newton (2010).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3299957&req=5

Figure 2: Structural domains of protein kinase C. The three classes of PKCs are shown. Members of each class have a catalytic domain that encompasses the C-terminus of the protein (shown in orange). Positions of residues in the catalytic domain that are phosphorylated during activation of the kinases are shown as yellow circles above each map. The threonine residue in the activation loop is the first to be phosphorylated, which allows phosphorylation of the threonine/serine in the turn motif and the serine/threonine in the hydrophobic motif, resulting in full activity of the kinase. There is no phosphorylation target in the atypical kinase hydrophobic motif; negative charge is supplied by the glutamic acid residue (indicated by the brown circle). The regulatory domains are located in the N-terminal half, and consist of C1 (blue), C2 (red) and pseudosubstrate domains (green). The positions of the C1 and C2 domains of conventional PKCs are reversed in the novel PKCs. Atypical PKCs lack a C2 domain, and have only a partial C1 domain. Redrawn from Steinberg (2008), Newton (2010).
Mentions: The cPKCs, nPKCs, and aPKCs have homologous catalytic kinase domains that encompass the C-terminal half of the molecules (Figure 2; Steinberg, 2008; Newton, 2010). The primary structure of this domain is well conserved between the proteins, and it includes essential sequence motifs that are common to all members as well as being required for maturation of the kinase. These motifs include the activation loop, which contains a threonine residue that generally must be phosphorylated for catalytic activity; in the case of PKCδ, phosphorylation of this site is observed, but it is not essential. Phosphorylation of the activation loop threonine is otherwise the essential first step in maturation of the newly synthesized protein. All members have both a turn motif and a C-terminal hydrophobic motif; each motif contains serine or threonine targets for autophosphorylation, a requirement for full maturation of the enzyme. One exception is noted for the atypical kinases, which have glutamic acid, an amino acid known to mimic phosphoSer/Thr, at the hydrophobic motif phosphoacceptor site. Phosphate incorporated during the maturation process remains an integral part of the protein, with little or no turnover.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry Rochester, NY, USA.

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.

No MeSH data available.


Related in: MedlinePlus