Phorbol esters receptors

In contrast to the TPA-type tumor promoters, palytoxin, thapsigargin, and okadaic acid are classified as non-TPA type tumor promoters, which do not bind to phorbol ester receptors, or activate protein kinase C in vitro (Table II) (6,25-27). In this chapter, thapsigargin is not discussed, because it is derived from terrestrial plants. 

Berkow RL, Kraft AS (1989) Bryostatin, a nonphorbol macrocyclic lactone activates intact human polymorphonuclear leukocytes and binds to the phorbol ester receptor. Biochem Biophys Res Commun 131 1109-1115... 

Hait WN, DeRosa WT (1991) The role of the phorbol ester receptor/protein kinase C in the sensitivity of leukemic cells to anthracyclines. Cancer Commun 3 77-81 Hallahan OE, Virudachalam S, Schwartz JL, Panje N, Mustafi R, Weichselbaum RR (1992) Inhibition of protein kinases sensitizes human tumor cells to ionizing radiation. RadiatRes 129 345-350... 

P. J. Parker, L. Coussens, N. Totty, L. Rhea, S. Young, E. Chen, S. Stabel, M. D. Waterfield, A. Ullrich (1986). The complete primary structure of protein kinase C, the major phorbol ester receptor. Science 233 853-859. 

As morusin (3) was assumed to interact with the phorbol ester receptor, we examined whether it inhibited the activation of protein kinase C by teleocidin in vitro [73]. Fig. (9) shows that morusin (3) inhibited the phosphorylation of histone type III-S by protein kinase C dose-dependent and that 80 pmol/L morusin caused 50% inhibition. 

Ron, D. and Kazanietz, M.G. (1999) New insights into the regulation of protein kinase C and novel phorbol ester receptors. FASEB ]., 13, 1658-1676. 

The structure of pendolmycin is closely related to the structures of tumour-promoting teleocidin and lyngbiatoxin (Fig. 15). Like tumour promoters pendolmycin binds to the phorbol ester receptor, and is an activator of protein kinase C. Pendolmycin suppresses EGF receptor tyrosine kinase by stimulating phosphorylation of EGF receptor, resulting in inhibition of EGF-induced PI turnover in A431 cells (28). Thus, actually. 

What is the biological significance of non-kinase DAG/phorbol ester receptors ... 

Ahmed, S, Kozma, R, Monfries, C, Hall, C, Lim, HH, Smith, P and Lim, L (1990) Human brain n-chimaerin cDNA encodes a novel phorbol ester receptor. Biochemical Journal, 212, 767-773. 

N.E. Lewin, P.M. Blumberg, and E. Abushanab, Conformationally constrained analogues of diacylglycerol. Interaction of y-lactones with the phorbol ester receptor of protein kinase C, J. Am. Chem. Soc. 144 1061 (1992). 

Signoret N, Oldridge J, Pelchen-Matthews A, Klasse PJ, Tran T, Brass LF, Rosenkilde MM, Schwartz TW, Holmes W, Dallas W, Luther MA, Wells TN, Hoxie JA, Marsh M (1997) Phorbol esters and SDF-1 induce rapid endocytosis and down modulation of the chemokine receptor CXCR4. J Cell Biol 139 651-664... 

Ml and M3 receptors mediate the excitatory effects and since this postspike hyperpolarisation is blocked by phorbol esters and is therefore presumably dependent on IP3 production, one would expect it to be mediated through M] receptors (see above), especially as these are located postsynaptically. Unfortunately it does not appear to be affected by pirenzapine, the Mi antagonist. By contrast, muscarinic inhibition of the M current is reduced by the Mi antagonist but as it is not affected by phorbol esters is not likely to be linked to IP3 production, an Mi effect. 

The majority of these members are a receptor for phorbol esters, the tumor-promoting products obtained from croton oil. One of them, 12-O-tctradccanoylphorbol- 13-acetate (TPA), is a potent... 

Phorbol esters are promoters that interact with cellular receptors and activate protein kinase C. Usually protein kinase C is activated by Ca++ and diacylglycerol, both of which result from the hydrolysis of phosphoinositides catalyzed by phospholipase C. Phospholipase C is normally activated by several different growth factors. Thus phorbol esters bypass a tightly regulated step in the control of cell growth. Since protein kinase C phosphorylates various proteins, it is not known how this activity participates in establishing a cancerous line of cells. 

Zhang L, Yunkai Y, Mackin S et al. Differential p opiate receptor phosphorylation and desensitization induced by agonists and phorbol esters. J Biol Chem 1996 271 11449-11454. 

Activation of PI-PLC-linked receptors, such as the mAChR, results in increased PKC activity. Since the addition of phorbol esters, which are PKC agonists (see Ch. 20), results in phosphorylation of Raf, this mechanism may provide an explanation for the ability of PI-PLC-coupled receptors to activate MAPK. A recently discovered protein tyrosine kinase PYK2, which is enriched in the CNS, is also activated by PKC. Like PTK-X, PYK2 phosphorylates SHC and recruits the Grb2-SOS complex, which results in activation of the MAPK cascade. PYK2 is also activated by... 

Granas, C., Ferrer, J., Loland, C. J., Javitch, J. A. and Gether, U. N-terminal truncation of the dopamine transporter abolishes phorbol ester- and substance P receptor-stimulated phosphorylation without impairing transporter internalization. /. Biol. Chem. 278 4990-5000, 2003. 

Under basal conditions, PKC is predominantly a cytoplasmic protein. Upon activation by Ca2+ or DAG, the enzyme associates with the plasma membrane, the site of many of its known physiological substrates, including receptors and ion channels. In fact, the translocation of PKC from the cytoplasm to the membrane has long been used as an experimental measure of enzyme activation. Such translocation has often been assayed by phorbol ester binding phorbol esters are tumor-promoting agents that selectively bind to and activate PKC. The molecular basis of the translocation of PKC from the cytoplasm to the plasma membrane has been solved. Subsequent to activation, PKC binds with high affinity to a series of membrane-associated proteins, termed receptors for... 

NK cells express receptors for numerous monokines constitutively, and produce IFN-y and other NK-derived cytokines rapidly in response to stimulation by monokines [18, 19]. Freshly isolated CD56 "s human NK cells are the primary source of NK cell-derived immuno-regulatory cytokines, including IFN-y, TNF-(3 (lymphotoxin), IL-10, IL-13 and GM-CSF, whereas the CDSb NK-cell subset produces consistently negligible amounts of these cytokines following stimulation with recombinant monokines in vitro [20]. The production of cytokines by NK cell subsets was investigated following activation with phorbol esters (e.g. phorbol 12-myristate 13-acetate (PMA)) and ionomycin. 

Kazanietz MG, CalocaMJ, Eroles P, et al, Pharmacology of the receptors for the phorbol ester tumor promoters Multiple receptors with different biochemical properties, Biochem Pharmacol 6Q A 7— A2A, 2000. 

Caloca MJ, Fernandez N, Lewin NE, Ching D, Modali R, Blumberg PM, Kazanietz MG (1997) Beta2>chimaerin is a high affinity receptor for the phorbol ester tumor promoters. J Biol Chem 272 26488-26496... 

Molecular biology phorbol esters/Sigma 2000 diterp./carcinogens, NO promoters activators of protein kinase C pantrop. and tranpa te Euphorbiaceae, Ang. (also a standard for phorbol-class receptor in cancer studies)... 

Fig. 7.10. Functions and regulation of protein kinase C. Receptor-controlled signal pathways lead to formation of the intracellular messenger substances and diacylglycerol (DAG), that, like phorbol ester (TPA), activate protein kinase C (PKC). Translocation to the cell membrane is linked with activation of protein kinase C receptors for protein kinase C, the RACK proteins, are also involved. Substrates of protein kinase C are the MARCKS proteins and other proteins associated with the cytoskeleton. Other substrates are the Raf kinase (see Chapter 10) and the receptor for vitamin D3 (VDR, see Chapter 4).

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