Cell membrane, protein kinase translocation

MAPK translocates to the surface membrane before contraction and then redistributes to the cytoplasm coincident with muscle cell shortening. Protein kinase C inhibitors block these translocations, suggesting a role for PKC in the activation of MAPK. In further support of a role for PKC in this process, PKC translocates to the surface membrane at the same time as MAPK. 

Upon activation, neurons begin trafficking TRPVl to the membrane where the receptors become activated, desensitized and then recycled to the intracellular compartments. Translocation of TRPVl to the cell membrane occurs via SNARE (snapin and synaptotagmin IX)-mediated exocytosis [37]. Broadly speaking, activation involves phosphorylation by protein kinases (most notably, protein kinase A [PKA] and C [PKC]) and desensitization involves de-phosphorylation by phosphatases (e.g. calcineurin) [38]. Among PKC isozymes, PKCp seems to be of particular importance [39]. 

It is known that protein kinase C can phosphorylate a number of key oxidase components, such as the two cytochrome b subunits and the 47-kDa cytoplasmic factor. This process is prevented by protein kinase C inhibitors such as staurosporine (although it is now recognised that this inhibitor is not specific for protein kinase C), which also inhibits the respiratory burst activated by agonists such as PMA. However, when cells are stimulated by fMet-Leu-Phe, translocation of pAl-phox to the plasma membrane can occur even if protein kinase C activity is blocked - that is, phosphorylation is not essential for the translocation of this component in response to stimulation by this agonist. Similarly, the kinetics of phosphorylation of the cytochrome subunits do not follow the kinetics of oxidase activation, and protein kinase C inhibitors have no effect on oxidase activity elicited by some agonists -for example, on the initiation of the respiratory burst elicited by agonists such as fMet-Leu-Phe (Fig. 6.14). Furthermore, the kinetics of DAG accumulation do not always follow those of oxidase activity. Hence, whilst protein kinase C is undoubtedly involved in oxidase activation by some agonists, oxidase function is not totally dependent upon the activity of this kinase. 

The interaction of the Pycomplex with G-protein coupled receptor kinases (see 5.3.4, P-adrenergic receptor kinase, PARK) appears to be of special regulatory importance. The function of the Py-complex in this system is shown in Fig. 5.9. The Py-complex binds specifically to the PARK and translocates this to the cell membrane. The translocation of PARK is necessary to switch off and modulate signal transmission via adrenaline. 

The PI3 kinase (PI3-K) is translocated to the membrane by interaction of the SH2 domain of its p85 subunit with phosphotyrosine residues of the activated receptor. There it converts PtdIns(3,4)P2.into PtdIns(3,4,5)P3 which binds to PH domains of various effector molecules and recruits them into the signaling chain. The effector molecules can stimulate cell division or can induce the programmed cell death. The tumor suppressor PTEN hydrolyses phosphates from PtdIns(3,4,5)P3 and thus inhibits the growth promoting effect of the PI3 kinase signaling. An important effector of PI3 kinase is the protein kinase Akt which is also termed protein kinase B (PKB). GF growth factor GFR growth factor receptor. 

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).

Hydroquinone (50 (.miol/L) induced a cytosol-to-membrane translocation of protein kinase C, followed by inactivation of the enzyme activity, in cultured LL/2 lung carcinoma cells (Gopalakrishna et al., 1994). 

Shoji-Kasai Y, Itakura M, Kataoka M et al (2002) Protein kinase C-mediated translocation of secretory vesicles to plasma membrane and enhancement of neurotransmitter release from PC 12 cells. Eur J Neurosci 15 1390-4... 

Simulation of glucose transport and glucose transporter translocation from intracellular stores to the plasma membrane in muscle cells by vanadate and peroxovan-adate involve a mechanism independent of PI-3K and protein kinase C systems utilized for stimulation of these processes by insulin. The transport of GLUT4 to the plasma membrane in muscle cells growing in culture after stimulation by vanadate, peroxovanadate, or insulin all require an intact actin network [138], Sometimes, the insulin-like action of vanadium is accompanied by overall stimulation of actual metabolic pathways. One example of this is the stimulation of the pentose phosphate pathway observed when vanadate promotes the incorporation of glucose into lipids, an antilipogenic effect [139],... 

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