Multiple, Distinct Forms of Bovine and Human Protein Kinase C Suggest Diversity in Cellular Signaling Pathways

Coussens, Lisa M.; Parker, Peter J.; Rhee, Lucy; Yang‐Feng, Teresa L.; Chen, Ellson; Waterfield, Michael D.; Francke, Uta; Ullrich, Axel

doi:10.1126/science.3755548

Cited by 1,007 publications

(413 citation statements)

References 25 publications

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“…This pattern, which also appears as a tandem repeat in the N-terminal regulatory domain of all members of the protein kinase C family [35][36][37] and in phospholipase A2 [34], has been proposed as a structural element involved in interaction of proteins with phospholipid [34]. Homology with the protein kinase C gene in this region is not limited to the cysteines, especially for the sequence spanned by Cys-382 and Cys-390 (the third and fourth cysteines in this pattern) ( fig.2).…”

Section: Northern Blot Analysismentioning

confidence: 95%

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Expression of RNA transcripts for the postsynaptic 43 kDa protein in innervated and denervated rat skeletal muscle

Froehner

1989

FEBS Letters

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A cDNA clone encoding the mouse muscle postsynaptic 43 kDa protein was isolated and sequenced. The amino acid sequence of this protein, which is closely associated with nicotinic acetylcholine receptors at Torpedo electrocyte and vertebrate skeletal muscle synapses, is very similar in different species. A cysteine-rich region homologous to part of the regulatory domain of protein kinase C may be important in interactions of this protein with the lipid bilayer. RNA transcripts for the 43 kDa protein increase only 2-3-fold after denervation of rat skeletal muscle, in sharp contrast to the a-subunit of the muscle nicotinic receptor which increases more than 30-fold. Thus, the expression of these two proteins is regulated by different mechanisms.

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Section: Northern Blot Analysismentioning

confidence: 95%

“…Features common to the catalytic sites of protein kinases are also absent from 43 kDa protein [26]. The similarity between 43 kDa protein and the Nomenclature and sequences for protein kinase C were taken from the following sources: rabbit [35], bovine [36], human [36].…”

Section: Northern Blot Analysismentioning

confidence: 99%

Expression of RNA transcripts for the postsynaptic 43 kDa protein in innervated and denervated rat skeletal muscle

Froehner

1989

FEBS Letters

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“…This phosphorylation is followed by two autophosphorylations within the C-terminal domain on most isoforms. When objective sequence alignments are carried out, five variable regions within the conventional PKC gene encode isoform specificity [78,79]. The last variable region (V5) of PKCβ consists of 50-52 amino acids that are alternatively spliced and results in transcripts encoding two proteins [74,80].…”

Section: Pkcβiimentioning

confidence: 99%

Specific protein kinase C isoforms as transducers and modulators of insulin signaling

Sampson

Cooper

2006

Molecular Genetics and Metabolism

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Recent studies implicate specific PKC isoforms in the insulin-signaling cascade. Insulin activates PKCsα, βII, δ and ζ in several cell types. In addition, as will be documented in this review, certain members of the PKC family may also be activated and act upstream of PI3 and MAP kinases. Each of these isoforms has been shown one way or another either to mimic or to modify insulin-stimulated effects in one or all of the insulin-responsive tissues. Moreover, each of the isoforms has been shown to be activated by insulin stimulation or conditions important for effective insulin stimulation. Studies attempting to demonstrate a definitive role for any of the isoforms have been performed on different cells, ranging from appropriate model systems for skeletal muscle, liver and fat, such as primary cultures, and cell lines and even in vivo studies, including transgenic mice with selective deletion of specific PKC isoforms. In addition, studies have been done on certain expression systems such as CHO or HEK293 cells, which are far removed from the tissues themselves and serve mainly as vessels for potential protein-protein interactions. Thus, a clear picture for many of the isoforms remains elusive in spite of over two decades of intensive research. The recent intrusion of transgenic and precise molecular biology technologies into the research armamentarium has opened a wide range of additional possibilities for direct involvement of individual isoforms in the insulin signaling cascade. As we hope to discuss within the context of this review, whereas many of the long soughtafter answers to specific questions are not yet clear, major advances have been made in our understanding of precise roles for individual PKC isoforms in mediation of insulin effects. In this review, in which we shall focus our attention on isoforms in the conventional and novel categories, a clear case will be made to show that these isoforms are not only expressed but are importantly involved in regulation of insulin metabolic effects.

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“…These phosphates appear to turn over, whereas Thr 197 in the C-subunit seems to be a stable phosphorylation site. Based on sequence alignments, protein kinase C is another good candidate for having a stable phosphorylation site in this region (Coussens et al, 1986). The mitogen-activated protein kinases (MAP kinases) are regulated by the consec- utive phosphorylation of Tyr 183 and Thr 185 in this region by MAP kinase kinase (Haystead et al, 1992).…”

Section: Phosphorylationmentioning

confidence: 99%

Crystal structures of the myristylated catalytic subunit of cAMP‐dependent protein kinase reveal open and closed conformations

et al. 1993

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Three crystal structures, representing two distinct conformational states, of the mammalian catalytic subunit of CAMP-dependent protein kinase were solved using molecular replacement methods starting from the refined structure of the recombinant catalytic subunit ternary complex (Zheng, J., et al., 1993a, Biochemistry 32,2154-2161). These structures correspond to the free apoenzyme, a binary complex with an iodinated inhibitor peptide, and a ternary complex with both ATP and the unmodified inhibitor peptide. The apoenzyme and the binary complex crystallized in an open conformation, whereas the ternary complex crystallized in a closed conformation similar to the ternary complex of the recombinant enzyme. The model of the binary complex, refined at 2.9 A resolution, shows the conformational changes associated with the open conformation. These can be described by a rotation of the small lobe and a displacement of the C-terminal30 residues. This rotation of the small lobe alters the cleft interface in the active-site region surrounding the glycine-rich loop and Thr 197, a critical phosphorylation site. In addition to the conformational changes, the myristylation site, absent in the recombinant enzyme, was clearly defined in the binary complex. The myristic acid binds in a deep hydrophobic pocket formed by four segments of the protein that are widely dispersed in the linear sequence. The N-terminal40 residues that lie outside the conserved catalytic core are anchored by the N-terminal myristylate plus an amphipathic helix that spans both lobes and is capped by Trp 30. Both posttranslational modifications, phosphorylation and myristylation, contribute directly to the stable structure of this enzyme.

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Multiple, Distinct Forms of Bovine and Human Protein Kinase C Suggest Diversity in Cellular Signaling Pathways

Cited by 1,007 publications

References 25 publications

Expression of RNA transcripts for the postsynaptic 43 kDa protein in innervated and denervated rat skeletal muscle

Expression of RNA transcripts for the postsynaptic 43 kDa protein in innervated and denervated rat skeletal muscle

Specific protein kinase C isoforms as transducers and modulators of insulin signaling

Crystal structures of the myristylated catalytic subunit of cAMP‐dependent protein kinase reveal open and closed conformations

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