‘Crosstalk’: a pivotal role for protein kinase C in modulating relationships between signal transduction pathways

Abstract

Over the past 20 years we have seen a phenomenal increase in our understanding ofthe diversity and the molecular mechanism of action of signal transduction systems. Now we are faced with a cell being provided with a myriad of cell surface receptors, each connected to particular signal transduction systems. The very complexity of such systems, together with the need of the cell to monitor and respond to a variety of external stimuli, poses the question as to what overall controls are placed upon these various transduction mechanisms and how they might relate to each other. At one extreme, we can envisage that pathways might be isolated completely from each other and thus function in an an apparent 'vacuum'. On the other hand, we can envisage 'cross-talk' between the various pathways linking each into an adaptable network array. Such a network, linking distinct signalling systems, would offer the cell a sophisticated ability to sense multiple environmental signals impinging upon it, thus providing a means of adapting or regulating its response to a particular range of effectors. In this way the cell might respond to the relative concentrations of various signals, taking into account the particular point in time when it first experienced a specific signal, together with the absolute length of time it was exposed to it. Such parameters having markedly different effects on cellular behaviour. Thus one might envisage that both the 'quantity' and the 'quality' of information flowing through any particular signal transduction system might be altered by the functioning of other transduction systems which were linked to form such an interactive network. A cell controlled in such a fashion could be regarded as being capable of 'learning', Correspondence to

Diabetes induces selective alterations in the expression of protein kinase C isoforms in hepatocytes

“…Similar observations of crippled G~ function have also been seen in cells challenged with ligands which stimulate phospholipid metabolism or with DAG [13], suggesting that it is the activation of protein kinase C which provides the molecular basis of this phenomenon. Indeed, studies on hepatocytes [14,18,26,38], platelets [39 41] and U973 cells [42] have indicated that the c~-subunit of G~-2 may provide a target for phosphorylation of Gi-2.…”

“…In hepatocytes of streptozotocin-induced diabetic rats [25,26] there is a loss of Gi function which appears to result from both a reduction in the expression of Gi-2 and also its increased phosphorylation by protein kinase C. Treatment of a variety of different cell types with tumour promoting phorbol esters has been shown to lead to the loss of guanine nucleotide-elicited, G~-mediated inhibition of adenylate cyclase activity [13,37]. Similar observations of crippled G~ function have also been seen in cells challenged with ligands which stimulate phospholipid metabolism or with DAG [13], suggesting that it is the activation of protein kinase C which provides the molecular basis of this phenomenon.…”

“…There is now considerable evidence for the occurrence of 'cross-talk' between different signalling pathways [13,14]. This certainly occurs in hepatocytes, which provides a good example of the modulation of adenylyl cyclase and cyclic AMP metabolism by lipid signalling pathways exerting actions through PKC [13 17].…”

Treatment of intact hepatocytes with synthetic diacyl glycerols mimics the ability of glucagon to cause the desensitization of adenylate cyclase

“…this enzyme has been shown to attenuate the functioning of a variety of receptors. including G-protein-linked ones, by effecting their phosphorylation [4] and is activated upon an increase in intracellular diacylglycerol concentrations [21]. Indeed, we were able to demonstrate that incubation of intact hepatocytes with either OAG or DHG led to an apparent desensitization of adenylate cyclase ( fig.…”

Regulation of type V adenylyl cyclase by PMA‐sensitive and ‐insensitive protein kinase C isoenzymes in intact cells

“…Over years, numerous investigators have demonstrated that activation of PKC by phorbol esters alters the intracellular cAMP levels in various tissues and cultured cells. However, the direction and degree of this alteration have been variable among studies [1]. Investigators have tried to explain this variability by the different sites of interaction; PKC may phosphorylate multiple components within the cAMP signaling system, such as receptors, G proteins and AC [2][3][4][5].…”