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Pathophysiological Aspects of Non-Tyrosine Kinase Signal Transduction

Second messenger systems direct cell function by translating extracellular signals of hormones, neurotransmitters, growth factors and other mediators into cellular responses. Disturbances of signal transduction pathways should result in either inadequate, or signal-independent direction of the cellular signalling machinery. Any dysfunction of these pathways would therefore be expected to profoundly alter cellular function with regard to specialized cellular responses and to cell proliferation. This is indeed the case, as examples of such dysfunctions show. One group of disturbances results from a physical alteration of one of the components in the signal transduction chain causing either overactivation or dysruption of a normal response pathway. The G-protein modifications by bacterial exotoxins or somatic mutations provide an established example for these events. A second group of dysfunctions may be caused by second messenger alterations resulting from metabolic disturbances such as the direct generation of the second messenger lipid (diacylglycerol) from glucose under conditions of markedly elevated glucose concentrations in diabetes mellitus. This overview will not deal with signal transduction by the steroid receptor superfamily or the neurotransmitter receptors which constitute ionic channels. Elements of the Signal Transmission Machinery The non-tyrosine kinase signal transduction pathways to be discussed comprise the G-protein coupled receptors which direct adenylate cyclase, the phosphoinositide coupled, Ca + -mediated second messengers and the G-protein coupled voltage dependent Ca -channels. These systems share a general structure (Fig. 1): the receptors belong to a large family of molecules consisting of a single amino-acid chain which is folded seven times through the membrane. These receptors activate a further member in the chain of signal transduction: a G-protein. G-proteins are a large family of membrane proteins which bind guanine nucleotides, hence their name. With GTP bound, they are active. Due to an intrinsic GTPase activity, they cleave GTP to G D P . With G D P bound they are inactive. The GTPase function thus represents a shut-off mechanism for the receptor-mediated signal and turns out to be a particularly vulnerable function of G-proteins regarding pathophysiology. At present, 16 members of the Gprotein family have been cloned and differential splicing of the known genes further extends their number {Birnbaumer 1990; Simon, Strathmann and Gautam 1991). The receptor

Horm. metab. Res. 24 (1992) 219-224 © Georg Thieme Verlag Stuttgart • New York

catalyses binding of GTP to the specific G-protein is involved in this signalling system, and thereby activates it. Each type of receptor appears to interact with a specific set of G-proteins (Kleuss, Hescheler, Ewel, Rosenthal, Schultz and Wittig 1991). The active G-protein then interacts with the next downstream member in the signal transduction cascade. Depending on the specific receptor- and G-protein type, for example, adenylate cyclase can be activated by a G s - ("s" for stimulatory) or inhibited by a Gi-protein ("i" for inhibitory), a phospholipase-C can be activated by a G p -protein, or a voltage-dependent C a 2 + -channel may be inhibited by G 0 -proteins. The G-protein activates the enzyme generating the second messenger as an intracellular signal, i. e. cyclic adenosine monophosphate (cAMP) in the case of the adenylate cyclase, inositol-trisphosphate and diacylglycerol (DAG) in the case of phospholipase C, or inhibition of the voltage dependent Ca -channel by direct interaction of the channel with the G 0 -protein (for review see Birnbaumer 1990; Simon, Strathmann and Gautam 1991). The second messengers then perform diverse functions. In most cases, a protein kinase becomes activated, which phosphorylates specific cellular substrates. Numerous kinases have been identified to date. The cAMP activates a kinase of the protein kinase A family, diacylglycerol activates a kinase of the protein kinase C family and calcium activates a kinase of the C a 2 + /calmodulin-dependent protein kinase family (Hunter 1991).

Fig. 1 Outline of signal transduction from the receptor via a Gsalpha protein to the effector adenylate cyclase. The principal defect of the G-protein is indicated consisting of a cholera exotoxin induced ADPribosylation or a somatic mutation. Both modifications block the GTPase function of the G-protein and thereby elimit the shut-off mechanism.

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A. Pfeiffer and H. Schatz Medizinische Klinik und Poliklinik, Klinikum Bergmannsheil, Universitat Bochum, Bochum, Germany

220 Horm. metab. Res. 24 (1992) Diseases Affecting G-Protein Function

A. Pfeiffer and H. Schatz Hereditary Mutation of G-Proteins

In pseudohypoparathyroidism, a hereditary mutation for one of the cAMP-stimulating Gs-proteins reduces its expression to about 50% of normal levels (Patten, Johns, Valle, Eil, Gruppuso, Steele, Smallwood and Levine 1990; Weinstein, Gejman, Friedman, Kadowaki, Collins, Gershon and Spiegel 1990). The symptoms resulting from this parThe gain of function defect consists of an al- tial reduction of G s are probably due to the inability of some of teration of the G-protein which blocks its mechanism of inacti- the Gs-protein coupled receptors such as those of FSH, LH, vation, i. e. the GTPase function (Cassel and Selinger 1977). TSH, parathyroid hormone (PTH) and olfactory receptors to The G-protein can be activated by the hormone-stimulated re- activate adenylate cyclase. The actual pattern of symptoms obceptor, but the subsequent inactivation cannot take place. This served in individual patients, however, is highly instructive, results in a prolongation and persistence of the signal. If this because a large variability of symptoms is observed. This variaalteration is caused by the exotoxin of a noninvasive microor- bility seems to indicate a rather delicate balance which may ganism like vibrio cholerae, it will be limited strictly to the site exist among the various partners of coupling systems: the most of infection, i. e. the gut. The syndrome results from overacti- prominent defect is the loss of response to parathyroid horvation of the cAMP-system which — in this case — corresponds mone (PTH) with the associated disturbances of calcium balto activation of VIP- and PGE2-receptors, i. e. stimulation of ance. However, other endocrine systems like the thyroid and secretion and inhibition of resorption. This results in watery the gonads may display various degrees of hypofunction. The diarrhea with its consequences. Notably, the syndrome caused associated syndrome of Albright Hereditary Osteodystrophy, by overproduction of VIP due to a VIP-producing endocrine which includes altered dental and bone morphology, altered tumor, causes almost similar symptoms which is easily ex- body proportions and oligophrenia may be present in variable plained by the pathophysiologically identical mechanism, i. e. degrees, and in some cases, resistance of the kidney to PTH may be absent, despite full expression of Albrights Hereditary overproduction of cAMP. Osteodystrophy and the biochemical reduction of functional Cholera toxin causes ADP-ribosylation of the G s (named pseudo-pseudo-hypoparathyroidism). A 50% rearginine in position 201 of the Gs-protein. This same amino duction in G s in some cases still permits sufficient function of acid was also found to be mutated in the somatotroph cells of PTH in the kidney but not in bone, whereas in other cases, a the pituitary in some acromegalic patients by a somatic point completely defective response to PTH in the kidney is apparmutation in the codon of the Arg-201. In this case the disease is ent (Levine and Auerbach 1989). These variable syndromes also strictly limited to these cells resulting in overproduction of despite similar losses of Gs (Patten and Levine 1990) are not excAMP and in hypersecretion of growth hormone and hyper- plained at present. Possible explanations may assume that plasia of the cells causing a pituitary adenoma and the syn- plasticity in the coupling of receptors to the different splice drome of acromegaly. A second mutation with identical con- variants of G s exists which may depend on other components sequences was also found at the position Gln-227. This muta- of cellular signalling machines thereby conferring tissue spetion was named the gsp (pronounced gasp) oncogene (Landis, cificity. The possibility that two different nonallelic genes Masters, Spada, Pace, Bourne and Vallar 1989). It may not be could be involved in Gs-production has not been verified until restricted to the pituitary as it has been found in 3/31 thyroid present (Simon, Strathmann and Gautam 1991) and the role of carcinomas (Suarez, du Villard, Caillou, Schlumberger, splice variants is unclear. Finally, the defect may show mosaiParmentier and Monier 1991) and in goiters in areas of en- cism in different organs and thereby lead to variable losses of demic iodine deficiency (Goretski, Lyons, Roeher and Bourne Gs. 1991). Further tissues are likely to be identified. Defects of the more distal components of couA similar mutation may also occur in other G- pling systems, i. e. of adenylate cyclase or of phospholipase C proteins. It has been shown in Gi-proteins which thereby per- have not been described to date. Similarly, the protein kinases sistently inhibit adenylate cyclase {Wong, Federmann, Pace, mediating the signals of the second messengers cAMP (protein Zachary, Evans, Pouyssegur and Bourne 1991) and this muta- kinase A), diacylglycerol (protein kinases C) and inositoltris(Ca /calmodulin-dependent protein kition was seen in gonadal tissue. Other G-proteins may be phosphate/Ca nases) have not been shown to display mutational alterations speculated to be sensitive to similar mutations. in diseases until present. However, our knowledge of these Loss of function alterations of G-proteins are proteins at the molecular level is quite recent and few attempts induced by an exotoxin produced by Bordatella pertussis, per- to find such defects were as yet undertaken. One problem is, tussis toxin. It ADP-ribosylates the inhibitory G-protein Gi that it appears difficult to identify diseases with possible de(which mediates effects of opioids, somatostatin, alpha2-re- fects of these kinases. This is partly due to the considerable hetceptors, p2-receptors of pancreatic (3-cells etc) and thereby erogeneity of each type of kinase. For example, there are 8 subcauses at least some of the symptoms associated with pertussis types of protein kinase-C cloned to date (Nishizuka 1988; infection (Katada and Ui 1982). The toxins action was origi- Hunter 1991) and at least 9 subtypes of calcium/calmodulin nally identified due to its ability to enhance insulin secretion dependent protein kinases (Hunter 1991). The types of calfrom pancreatic islets in children with pertussis infections and cium/calmodulin-dependent kinases present in the human was therefore called "islet activating protein". Later it was have not been elucidated until present as only the non-human shown to ADP-ribosylate also some other G-proteins, with mammalian enzymes were characterized. The kinases are moreover widely distributed in the body, and the functions of similar consequences.

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Regarding pathophysiology, the G-proteins have clearly been linked to several diseases. These can be classified into such, where activation of the G-protein occurs, such as in cholera and acromegaly and into such with loss of function like pertussis and pseudohypoparathyroidism.

the various subtypes may partially overlap. The limitations of our knowledge make it difficult to predict symptoms which might result from a lack of one subtype of a protein kinase. As the example of pseudohypoparathyroidism shows, quite particular syndromes may result even from the lack of a widely distributed protein, depending on the irreplaceability of the subtype in a particular organ. One example of a disease with a hereditary defect most likely of a distal component of a coupling system is pseudohypoparathyroidism type II: in this variant, cAMP is generated by the kidney in response to PTH but a phosphaturic response is not generated. This suggests a defect distal to the generation of cAMP and possible components include adenylate cyclase or protein kinase A although other possibilities exist (Levine and Auerbach 1989). Regulation of Protein Kinase Activity by Environmental Factors Protein kinases undergo substantial modulations of their activities in response to their states of activation. Therefore, disturbances in the regulation of the activity of second messenger dependent protein kinases are likely to play an important role in some diseases. In fact, many diseases like, for example, development of colonic adenomas/carcinomas or insulin-dependent and non-insulin dependent diabetes mellitus, represent some form of interaction between environmental factors and hereditary predispositions. Environmental factors, in particular nutritional habits, may influence the expression of hereditary traits. Kinase activities may be affected by components like obesity and insulin resistance, circulating fatty acids and fats, carcinogens and tumor promoters, as some of the following examples show. Although the precise causes for activation or inhibition of protein kinases by environmental factors are not known, this approach is of considerable interest, also with regard to preventive strategies. Metabolically Altered Protein Kinase Activity A physiologic example of regulation of protein kinase C by a metabolic process was recently provided with the observation that prolonged starvation causes activation of protein kinase C in the liver of rats. The insulin receptor is a known substrate for protein kinase C which down-regulates its activity by serine-phosphorylation. Starvation induced a 45 % downregulation of the insulin stimulated autophosphorylation of the insulin receptor and doubled the activity of membrane associated protein kinase C (Karasik, Rothenberg, Yamada. White and Kahn 1990). Insulin receptor function normalized upon removal of the phosphate by treatment with a phosphatase. Protein kinase C thus mediates a desensitization of the insulin receptor in starved rats. A similar mechanism could quite well account for the insulin resistance seen in obese subjects which is reversible with weight loss although this remains to be demonstrated. Diabetic rats, however, did not show a protein kinase C-dependent desensitization of insulin receptors, indicating that other mechanisms may be operative in this condition {Karasik et al. 1990).

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Altered Kinase Activities in Diseases Alterations of kinase activities have been shown in numerous diseases although the clinical relevance is not proven. A defective insulin response of cyclic adenosine monophosphate (cAMP)-dependent protein kinase was shown in humans with insulin resistance and proposed to contribute to their reduced stimulation of skeletal muscle glycogen synthase (Kida, Nyomba, Bogardus and Mott 1991). Protein kinase C, was found to be overactivated compared to normals in fibroblasts from patients with psoriatic skin disease. Protein kinase-C was reported to undergo accelerated downregulation due to overactivity of specific proteases in a mouse model of Chediak-Higashi Syndrome (Sato, Tanabe, Ito, Ishida and Shigeta 1990). Similarly, colonic adenomas showed a loss of protein kinase C by almost 60 % (Kopp, Noelke, Sauter, Schildberg, Paumgartner and Pfeiffer 1991). This was previously observed in colonic carcinomas (Guillem, O'Brian, Fitzer, Forde, LoGerfo, Treat and Weinstein 1987). A similar pattern of loss of the activity of protein kinase-C was also observed during the initial stages in a model of colonic carcinoma, i. e. in rats treated with the carcinogen 1,2-dimethylhydrazine (Baum, Wall, Sitrin, Bolt and Brasitus 1990). Cellular levels of protein kinase C are highly regulated. Its activation results in binding of the cytosolic enzyme to the cell membrane. This appears to be followed by proteolytic degradation of the protein kinase C. Prolonged activation therefore results in a dramatic loss of activity. The downregulation seen in colonic adenomas, therefore, could in fact represent overactivation. To test this hypothesis, one may determine the levels of its endogenous activator, the second messenger diacylglycerol. Weinstein's group observed, that colonic bacteria of some individuals produce large amounts of this second messenger (Weinstein 1990). If this diacylglycerol became available to the colonic epithelial cells, one may expect such an overactivation. However, measurements of diacylglycerol showed, that levels are reduced in colonic carcinomas and adenomas (Sauter, Nerlich, Spengler, Kopp and Pfeiffer 1990; Phan, Morotomi, Guillem, LoGerfo and Weinstein 1991). The reduction in protein kinase C therefore appears to be an early event in the genesis of colonic adenomas and carcinomas. How could a loss of protein kinase C contribute to the development of colonic carcinomas? Weinstein's group has approached this question by transfecting human colonic HT-29 carcinoma cells with a protein kinase C of the |31-subtype (Choi, Tchou-Wong and Weinstein 1990). These cells expressed 11 —15-fold higher levels of protein kinase C than the normal HT-29 cells and showed a marked inhibition of growth, a reduced tumorigenesis in nude mice and loss of anchorage independent growth in soft agar. Protein kinase C thus behaved as a growth inhibitor and antioncogene in these cells. Its loss, which is observed in small adenomas, may promote the development of colonic adenomas and the progression to carcinomas at a very early stage. The cause for its loss, however, remains unclear at present. Later stages of colonic adenomas and carcinomas have been linked to activation of the ras-oncogene, allelic mutation of the dimeric antioncogene p53 and to deletion of various putative antioncogenes (Fearon and Vogelstein

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Non-Tyrosine Kinase Signal Transduction

1990). These genetic alterations, however, rather represent sequelae of an initial oncogenic process. Linkage analysis has localized a genetic alteration to the region of chromosome 5q21—22 in patients with a hereditary form of colonic carcinoma, familial adenomatous polyposis coli. Although genes from this region were partially cloned in a tremendous effort, the primary site of mutation or deletion is still unclear. However, oncogenesis is thought to progress through distinct stages of initiation, promotion and progression and it appears not unlikely, that a loss of protein kinase C is involved in the promotion of colonic neoplasms even though the initiating event may be distinct {Weinstein 1990). Diabetic Complications Major complications of longstanding diabetes mellitus are the secondary diseases such as angiopathy, nephropathy, neuropathy and retinopathy which are most likely a consequence of the chronically elevated levels of blood glucose. Glucose appears to directly interact with two second messengers, inositol-trisphosphate and diacylglycerol (Fig. 2). The secondary complications of diabetes mellitus therefore are candidate diseases which may involve a metabolically induced dysregulation of second messengers.

Fig. 2 Changes in the protein kinase-C branch of the phosphoinositol-second messenger system by elevated blood glucose levels: Normal signal transduction proceeds from the receptor through a G-protein to phospholipase-C which generates the second messengers diacylglycerol and inositol-trisphosphate (not shown). In the presence of elevated levels of blood glucose, diacylglycerol can be generated via cellular glucose metabolism in susceptible tissues and causes a direct activation of protein kinase-C (see text).

A. Pfeiffer and H. Schatz It has long been known, that polyols like sorbitol and dulcitol are produced from glucose by the enzyme aldose reductase under conditions of hyperglycemia {Greene, Lattimer and Sima 1987). In early diabetic humans and acutely diabetic rats, a rapidly reversible slowing of nerve conduction occurs which possibly reflects biochemical abnormalities related to the development of diabetic neuropathy. This has been linked to activation of the polyol pathway by glucose and secondary alterations in the metabolism of myo-inositol and phosphoinositides leading to an impairment of the production of phosphatidyl-inositol. Since this phospholipid is the precursor from which the second messengers diacylglycerol and inositol-polyphosphates are generated it was reasonable to link a reduction of the peripheral nerve Na + -K + ATPase activity to a lack of phosphoinositide derived second messengers. Indeed, the experimentally induced defect is normalized by either dietary supplementation of myo-inositol or the administration of aldose reductase inhibitors, which also normalize peripheral nerve Na + -K + -ATPase activity {Greene, Lattimer and Sima 1987). The second messengers of the phosphoinositide pathway activate either the calcium/calmodulin dependent pathway or protein kinase-C. A deficient activation of protein kinase-C was therefore postulated to account for the deficient activation of peripheral nerve Na + K + -ATPase. Kim, Kyriazi and Greene (1991) recently demonstrated that protein kinase C agonists were able to reverse the deficit of peripheral nerve Na -K -ATPase activity in vitro in membrane fractions from sciatic nerves of streptozotocin diabetic rats. This sequence of events may be particular to tissues which are dependent on the supply of myo-inositol from external sources {Greene et al. 1987). In other tissues, recent evidence suggested an overactivation of protein kinase C rather than a loss of activity in the presence of elevated glucose. This agrees with the considerable heterogeneity of functions of second messengers in different cell types. In cultured bovine retinal endothelial cells a high-glucose-induced decrease in Na + -K+ -ATPase activity has been demonstrated which was reversed by aldose reductase inhibitors. However, in contrast to the situation in peripheral nerves, protein kinase C was activated due to an increase in diacylglycerol and there was no evidence for a loss of phosphatidyl-inositols in the cell membranes {Lee, MacGregor, Fluharty and King 1989). The increase in diacylglycerol was probably due to direct synthesis from glucose {Dunlop and Larkins 1985) and was also observed in other tissues like pancreatic islets {Peter-Riesch, Fathi, Schlegel and Wollheim 1987) or vascular smooth muscle {Lee, Saltsman, Ohashi and King 1989). The increased metabolism of glucose in the presence of hyperglycemia leads to 2—3-fold elevations of DAG which correlates with activation of this enzyme. Similar observations have been made in renal glomeruli {Craven and DeRubertis 1989) and in rat myocardium {Okumura, Akiyama, Hashimoto, Ogawa and Satake 1988). A rat skin chamber model was used to assess functional changes associated with such an activation of protein kinase C in vivo using either high glucose or protein kinase C activators {Wolf, Williamson, Easom, Chang, Sherman and Turk 1991). In this model increased albumin fluxes across microvasculature and increased blood flow were seen after either method to enhance the activity of protein kinase C. This increased vascular leakiness was taken as a correlate of diabetic vasculopathy. The fluxes of albumin in response to glucose were prevented by treatment with

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a membrane protein. Proc. Natl. Acad. Sci. USA 79: 3129-3133 (1982) Kida, Y., B. L. Nyomba, C. Bogeradus, D. M. Mott: Defective insulin response of cyclic adenosine monophosphate-dependent protein kinase in insulin resistant humans. J. Clin. Invest. 87: 673-679 (1991) Kim, J., H. Kyriazi, D. G. Greene: Normalization of Na + -K+ -ATPase activity in isolated membrane fraction from sciatic nerves of streptozotocin-induced diabetic rats by dietary myo-inositol supplementation in vivo or protein kinase C agonists in vitro. Diabetes 40:558-567(1991) Kleuss, C, J. Hescheler, C. Ewel, W. Rosenthal, G. Schultz, B. Wittig: Assignment of G-protein subtypes to specific receptors inducing inhibition of calcium currents. Nature 353:43—48 (1991) Kopp, R., B. Noelke, G. Sauter, F. W. Schildberg, G. Paumgartner, A. Pfeiffer: Altered levels of protein kinase C activity in biopsies of human colonic adenomas and carcinomas. Cancer Res. 51: 205— 210(1991) Landis, C. A., S. B. Masters, A. Spada, A. M. Pace, H. R. Bourne, L. Villar: GTPase-inhibiting mitations activate the alpha chain of G s and stimulate adenylate cyclase in human pituitary tumors. Nature 340: 692-696 (1989) Lee, T.S., L. C. MacGregor, S. J. Fluharty, G. L. King: Differential Taken together, there is some evidence, that hyregulation of protein kinase C and (Na,K)-adenosine triperglycemia results in activation of protein kinase C in several phosphatase activities by elevated glucose levels in retinal capiltissues by increased formation of the second messenger diacyllary endothelial cells. J. Clin. Invest. 83:90-94 (1989) glycerol and that this may play a role in the development and Lee, T S., K. A. Saltsman, H. Ohashi, G. L. King: Activation of protein progression of diabetic complications. Its role in humans rekinase C by elevation of glucose concentration: proposal for a mains to be investigated. mechanism in the development of diabetic vascular complications. Proc. Natl. Acad. Sci. USA 86:5141-5145 (1989) Levine, M. A., G. D. Auerbach: Pseudohypoparathyroidism. In: EnReferences docrinology. L. J. DeGroot Ed., Saunders, Philadelphia (1989), pp. 1065-1079 Baum, C. L., R. K. Wali, M. D. Sitrin, M. J. Bolt, T. A. Brasitus: 1,2Nishizuka, TV. .'The molecular heterogeneity of protein kinase C and its dimethylhydrazine-induced alterations in protein kinase C activiimplications for cellular regulation. Nature 334: 661—665 (1988) ty in the rat preneoplastic colon. Cancer. Res. 50: 3915-3920 Okumura, K. N., H. Akiyama, K. Hashimoto, K. Ogawa, T. Satake: (1990) Alterations of 1,2-diacylglycerol content in myocardium from diaBirnbaumer, L.: Transduction of receptor signal into modulation of efbetic rats. Diabetes 37: 1168-1171 (1988) fector activity by G-proteins: The first 20 years or so . . . FASEB J. Patten, J. L., D. R. Johns, D. Valle, C. Eil, P. A. Gruppuso, G. Steele, P. 4: 3068-3078 (1990) M. Smallwood, M. A. Levine: Mutation in the gene encoding the Cassel, D., Z. Selinger: Mechanism of adenylate cyclase activation by stimulatory G-protein of adenylate cyclase in Albright's hereditary cholera toxin: inhibition of GTP hydrolysis at the regulatory site. osteodystrophy. N. Engl. J. Med. 322: 1422-1419 (1990) Proc. Natl. Acad. Sci. USA 74:3307-3311(1977) Choi, P. M., K.-M. Tchou-Wong, I. B. Weinstein: Overexpression of Patten, J. L., M. A. Levine: Immunochemical analysis of the alphasubunit of the stimulatory G-protein of adenyl-cyclase in patients protein kinase C in HT-29 colon cancer cells causes growth inhibiwith Albright's hereditary osteodystrophy. J. Clin. Endocrinol. tion and tumor suppression. Mol. Cell. Biol. 10:4650-4657 (1990) Metab. 71: 1208-1214(1990) Craven, P. A., F. R. DeRubertis: Protein kinase C is activated in glomPeter-Riesch, B., M. Fathi, W. Schlegel, C. B. Wollheim: Glucose and eruli from streptozotocin diabetic rats. J. Clin. Invest. 83: 1667carbachol generate 1,2-diacylglycerol by different mechanisms in 1675(1989) pancreatic islets. J. Clin. Invest. 81:1154-1161 (1988) Dunlop, M. E., R. G. Larkins: Pancreatic islets synthesize phosPhan, S. C, M. Morotomi, J. G. Guillem, P. LoGerfo, I. B. Weinstein: pholipids de novo from glucose via acyl-dihydroxyacetone Decreased levels of 1,2-sn-diacylglycerol in human colon tumors. phosphate. Biochem. Biophys. Res. Commun. 132: 467-473 Cancer Res. 51: 1571-1573(1991) (1985) Sato, A., F. Tanabe, M. Ito, E. Ishida, S. Shigeta: Thiol proteinase inFearon, E. R., B. Vogelstein: A genetic model for colorectal hibitors reverse the increased protein kinase C down-regulation tumorigenesis. Cell 61: 759-767 (1990) and concanavalin A cap formation in polymorphonuclear leukoGoretzki, P. E., J. Lyons, H. D. Roeher, H. R. Bourne: Mutational acticytes from Chediak-Higashi syndrome (Beige) mouse. J. Leukovated Gs-protein (GSP) — determination for multinodular goiters. cyte Biol. 48: 377-381 (1990) Acta Endocrinol. Suppl. l,Vol. 124: A30 (1991) Greene, D. A., S. A. Lattimer, A. A. F. Sima: Sorbitol, phosphoinosi- Sauter, G., A. Nerlich, U. Spengler, R. Kopp, A. Pfeiffer: Decreased levels of diacylglycerol in adenomas and carcinomas of the colon. tides and sodium-potassium-ATPase in the pathogenesis of diaGut 31: 1041-1045(1990) betic complications. N. Engl. J. Med. 316:599 - 606 (1987) Simon, M. I., M. P. Strathmann, N. Gautam: Diversity of G-proteins Guillem, J. G., C. A. O'Brien, C. J. Fitzer, K. A. Forde, P. LoGerfo, M. in signal transduction. Science 252:802-808 (1991) Treat, I. B. Weinstein: Altered levels of protein kinase C and Ca 2+ Suarez, H. G., J. A. du Villard, B. Caillou, M. Schlumberger, C. dependent protein kinases in human colon carcinomas. Cancer Parmentier, R. Monier: GSP-mutations in human thyroid tumors. Res. 47: 2036-2039 (1987) Oncogene 6: 677-679 (1991) Hunter, T: Protein kinase classification. In: Methods in Enzymology, Testamariam, B., M. L. Brown, R. A. Cohen: Elevated glucose impairs Vol. 200, Protein phosphorylation. T. Hunter, B. M. Sefton (eds.), endothelium-dependent relaxation. J. Clin. Invest. 87: 1643 — 1648 Academic Press, San Diego (1991), pp. 3 - 37 (1991) Karasik, A., P. L. Rothenberg, K. Yamada, M. F. White, C. R. Kahn: Weinstein, L. S., P. V. Gejman, E. Friedman, T. Kadowaki, R. M. ColIncreased protein kinase C activity is linked to reduced insulin relins, E. S. Gershon, A. M. Spiegel: Mutations of the Gs alpha-subceptor autophosphorylation in liver of starved rats. J. Biol. Chem. unit gene in Albright's hereditary osteodystrophy detected by 265: 10226-10231 (1990) denaturing gradient gel electrophoresis. Proc. Natl. Acad. Sci. Katada, T, M. Ui: Direct modification of the membrane adenylate cyUSA 87: 8287-8289 (1990) clase system by islet activating protein due to ADP-ribosylation of

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staurosporine, a potent but unselective inhibitor of protein kinase C and they were mimicked by an activator of protein kinase C, the phorbol ester TPA (Wolf et al. 1991). A further aspect to the pathological activation of protein kinase C by elevated glucose was recently provided by Testamariam, Brown and Cohen (1991). They reported that muscarinic receptormediated endothelim-dependent relaxation of rabbit aorta exposed to elevated glucose was impaired which is known for aorta from diabetic animals. This impairment of relaxation was also inducible with agonists of protein kinase C and was reversed by treatment with inhibitors of protein kinase C. They moreover demonstrated that protein kinase C induced the formation of vasoconstrictor prostanoids, including thromboxane A2, in the aorta. Since these prostanoids are also implicated in platelet aggregation and smooth muscle proliferation, they provide a conceptual link to the development of thrombotic and atherosclerotic vascular disease and diabetic vasculopathy.

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Weinstein, I. B.: The role of protein kinase C in growth control and the Requests for reprints should be addressed to: concept of carcinogenesis as a progressive disorder in signal transduction. In: The biology and medicine of signal transduction. Y. A.Pfeiffer Nishizuka (ed.), Raven Press, New York (1990),pp.307-316 Medizinische Klinik und Poliklinik Wolf, B. A., J. R. Williamson, R. A. Easom, Chang, W. R. Sherman, J.Klinikum Bergmannsheil Turk: Diacylglycerol accumulation and microvascular abnormalitiesUniversitat Bochum induced by elevated glucose levels. J. Clin. Invest. 87:31—38 (1991) Gilsingstr. 14 Wong, V. H., A. Federman, A. M. Pace, I. Zachary, T. Evans, J. PouysD-4630 Bochum (Germany) segur, H. R. Bourne: Mutant alpha subunits of Gi2 inhibit cyclic AMP accumulation. Nature 351:63-65 (1991)

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219 Pathophysiological Aspects of Non-Tyrosine Kinase Signal Transduction Second messenger systems direct cell function by translating extracellular...
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