Co/iyrijihr {(•")
Esp ncrmalol IW:: I' 2117 220 Primed ill Dfilimirk . Ail riyiiis n'scni'ii
1992
ISSN
Review Article
Studies and perspectives of signal transduction in the skin Inohara S. Studies and perspectives of signal transduction in the skin. Exp Dermatol 1992: 1: 207-220. iQ Munksgaard, 1992 Abstract: Tumor-promoting phorbol ester and epidermal growth factor (EGF) exert marked intluences on the proliferation and differentiation of keratinocytes. These two agents bring their physiological functions into play via protein kinase C (PKC) activation (and/or down regulation) and protein tyrosine kinase, respectively. In this paper, the present situation in the studies on the signal transduction of keratinocytes centering around these two kinases is discussed. An outline of studies on signal transduction of cells other than keratinocytes in the skin is also given.
Introduction Studies on signal transduction made explosive progress centering around protein phosphorylation in 1980s. In the domain of dermatology, too, many new findings have been reported. In this paper I give an outline of studies in dermatology, together with the results of studies in basic science, and present the outlook for the future. To begin with, a history of studies on signal transduction and an outline of modes of signal transduction which have been established up to the present (Fig. 1) will be mentioned. The first step in studies in this field was the discovery of cAMP by Sutherland (1). That is, the tnechanism has been made clear whereby sigtials frotn outside cells such as hormones combine with the receptor of cells to increase cAMP in cells. In 1968, the group of Krebs discovered cAMP-dependent protein kinase (Protein kinase A, PKA) (1). Studies made thereafter revealed that the intracellular action of cAMP is exerted via activation of PKA. However, it has also been discovered that many extracellular signals do not go through the route of the cAMP-PKA system. And it has long been known that many of those signals degrade inositol phospholipids (PI) of cell tnembranes (2, 3). The physiological meaning of this retrained unknown for a long time. In 1980s, however, it was found that diacylglycerol, a metabolite of PI, activates protein kinase C (PKC) and that inositol triphosphate (IP^), the another metabolite of PI, mobilizes intracellular Cir^ (4-6) (Fig. 1). Furthei tnore, it has also been shown thai
Shinichi Inohara Department ol Dermatology, Hyogo College of Medicine, Hyogo, Japan
Key words: skin - protein kinase C - protein tyrosine kinase - phosphorylation Shinichi Inohara. M.D., Department of Dermatology. Hyogo College of Medicine. Nishinomiya, Hyogo 663. Japan Accepted for publication 15 January 1993
Ca-^ cotnbine with calmodulin (CDR) to activate Ca'+ and CDR-dependent protein kinase. Therefore it has been made clear that these kinases are activated by metabolites of PI to have information ttansmitted into the inside of cells (Fig. 1). The signal transduction composed mainly of these kinases was at first thought to be concerned with the short-tertn reactions of hormones and neurotransmitters. Recently, however, it has becotne clear that these kinases are concerned with long-term reactions, such as proliferation, differentiation and oncogenesis as well and this has become particularly evident in PKC. ln 1982 it was discovered that tumor-promoting phorbol esters activate PKC directly without taking part in the degradation of PI (7). Furthertnore, studies conducted subsequently have tevealed that PKC is itself the receptor of phorbol esters (8). Since phorbol esters exert marked effects on proliferation, differentiation and oncogenesis, there is a strong possibility that PKC is concerned with such long-lertn reactions. Further, it has also been confirmed that various growth factors such as platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) have PI degradating ability (9). Accordingly, PKC is thought to serve as the focus of action for those growth factors. ^ PKA, PKC, Ca=+ and CDR-dependent PK are protein kinases that phosphorylate serine and threonine of protein, i.e. are serine-threonine kinases. In the 1980s, the presence of protein kinase that phosphorylates tyrosirie, that is protein tyrosine kinase (PTK), was demonsttated (10, 11). To begin 207
Inohara with, it was proven by the group of Hunter that p60''""', a product of v-.src which was an oncogene of Rous sarcoma virus, had PTK activity (10). Furthermoi"e, it became clear that many of the other oticogene products also had PTK activity (11) and that the receptors for various growth factors also had PTK activity (11, 12). Therefore, PTK might be an enzyme that is closely related to proliferation. Phorbol ester being a tumor promoter in mouse epidermis exerts marked effects on proliferation, differentiation and tumorigenesis of the epidermis (13). Epidermal growth factor (EGF) whose receptor has PTK activity also exerts marked effects on proliferation and differentiation in the epidermis (14). Therefore, it is highly possible that serinethreonine kinases, mainly PKC and PTK, play important roles in proliferation, differentiation and tumorigenesis of keratinocytes. Now mention will be made of studies mainly on signal transduction of keratinocytes and also of cells other than keratinocytes in the skin. (Fig. 1 illustrates main route of signal transduction to be described later). I. Signal transduction in keratinocytes 1) Proliferalicm atul differentiation i) cAMP-PKA system: What first attracted attention in the studies on signal transduction in keratinocytes was a study of the cAMP-PKA system. cAMP has attracted attention in dermatology since Voorhees' report that cAMP is decreased in psoriatic epidermis compared with normal epidermis (15). At that time, cAMP was thought to act in suppressing proliferation; so, hyperproliferation of
Hormone etc
I'horbol ester j
PKC
i, ®1)rotein (Ser, Thr)
C a " CDR d e p t .
Drotein (Ser. Thr)
fos.
(J>protein CSer. Tlir)
Tt \
IPTK
(J^protein (Tyr)
jun
NUCLEUS
Figure !. Authentic scenario of signal transduction. G protein: GTP-bindiiig protein, PI: inosilol plio.spholipids, DG: diacylglycerol, IP': inositol triphosphale. PKA: protein kinase A, PKC: protein kinase C. PTK: protein lyro.sine kina.se. C1815-1818. 2. Flokin M R, Hokin L E. Enzyme secretion and the incorporation of '-P into phospholipids of pancreatic slices J Biol Chem 1953: 203: 967-977. 3. Michell R H. Inositol phospholipids and cell surface receptor function. Biochim Biophys Acta 1975: 415: 81-147. 4. Kikkawa U, Takai Y, Minakuchi R, Inohara S, Nishizuka Y. Calcium-activated, phospholipid-depcndent protein kinase from rat brain, subecllular distribution, purification, and properties. J Biol Chem I98T- '>5713341-13348. 5. Nishizuka Y. The role of protein kinase C in cell surface signal transduction and tumor promotion Nature 1984308: 693-698. 6. Berridge M J, Irvine R F. Inositol triphosphate, a novel second messenger in cellular signal transduction Nature 1984: 312: 315-324. 7. Castagna M, Takai Y, Kaibuchi K, Sano K, Kikkawa U, Nishizuka Y. Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol ester. J Biol Chem 1982: 257: 7847-7851. 8. Nishizuka Y Studies and perspectives of protein kinase C. Science 1986: 233: 305-312. 9. Berridge M J. Inositol lipid and cell pioliferation. Biochim Biophys Aeta 1987: 907: 33-45. 10. Hunter T, Scfton B W. Transforming gene product of rous sarcoma virus phosphorylates tyrosine. Proc NatI Acad Sci USA 1980: 77: 1311-1315. 11. Hunter T. Cooper J A. Protcin-tyrosine kinases. Ann Rev Biochem 1985: 54: 897-930. 12. Ushito H, Cohen S. Identification of phosphotyrosine as a product of epidermal growth factor-activated protein kinase in A-431 cell membranes. J Biol Chem 1980- "'558363-8365. 13. Yuspa S H. Tumor promotion in epidermal cells in culture. In Slaga T J, ed. Mechanism of Tumor Promotion, vol in Tumor Promotion and Careinogenesis in Vitro Boca Raton, Fla: CRC Press, 1984: 1-11. 14. Yates R A, Nanney L B, Gates R E, King L E. Epidermal growth factor and related growth factors. Int I Dermatol 1991: 687-694.
Signal transduction in skin 1 5. Voorhees J J, Duell E A. Psoriasis as a possible defect of the adenyl cyclasc-cyclic AMP cascade. Arch Dermatol 1971: 104: 352-358. 16. Green H. Cyclic AMP in relation to proliferation of the epidermal cell: a new view. Cell 1978: 15: 801-811. 17. Okada N, Kitano Y, Ichihara K. Effects of cholera toxin on proliferation of cultured human keratinocytes in relation to intracellular cyclic AMP levels. .1 Invest Dermatol 1982: 79: 42^7. 18. Adachi K. lizuka H, Halprin K M, Levine V. Epidermal cyclic AMP is not decrea.sed in psoriatic lesions. J Invest Dermatol 1980: 74: 74-76. 19. Inohara S, Sagami S. Phosphorylation of epidermal keratin proteins by cyclic AMP-dependent protein kinase. Arch Dermatol Res 1983: 275: 417^18. 20. Ikai K, McGuire J. Phosphorylation of keratin polypeptidcs. Biochim Biophys Acta 1983: 760: 371-376. 2 1 . Yoshikawa K, Takeda J, Ncmoto O, Uo T Halprin K M, Adachi K. Phosphorylation of pig epidermal soluble protein by endogeneous cAMP-dcpendent protein kinase. J Invest Dermatol 1983: 80: 108-111. 22. Edinger F M, Penn A. Tumor promoter-stimulated protein phosphorylation in mouse epidermis is inhibited by bromophenacyl bromide. J Invest Dermatol 1985: 84: 413-416. 23. Koizumi H, Aoyagi T, Ohkawara A. Phosphorylation of soluble pig epidermal proteins by endogeneous calciumactivated, phospholipid-dependent protein kinase. Arch Dermatol Res 1986: 279: 95-99. 24. Gschwendt M, Kittstein W, Marks F. A novel type of pborbol ester-dependent protein phosphorylation in the particulate fraction of mouse epidertnis. Biochem Biophys Res Commun 1986: 137: 766-114. 25. Chida K, Tsunenaga M, Kasahara K, Kohno Y, Kuroki T. Regulation of creatinine phosphokinase B activity by protein kinase C. Biochem Biophys Res Commun 1990: 173: 346-350. 26. Smith B M. Colburn N H. Protein kinase C and its substrates in tumor promoter-sensitive and -resistant cells. J Biol Chem 1988: 263: 6424-6431. 27. Takahashi M, Tezuka T, Towatari T, Katunuma N. Identification of hematoxylin-stainable protein in epidermal keratohyalin granule as phosphorylated cystatin a by protein kinase C. FEBS LeU 1991: 287: 178-180. 28. Chakravarty R. Rong X, Rice R H. Phorbol estet-stitnulated phosphorylation of keratinocyte transglutaminase in the membrane anchorage region. Biochem J 1990: 271: 25-30. 29. Kasahara K. Chida K, Tsunenaga M, Kohno Y, lkuta T Kuroki T Identification of lamin B, as a substrate of protein kinase C in BALB/MK-2 mouse keratinocytes. J Biol Chem 1991: 266: 20018-20023. 30. Aoyagi T, Suya H, Umeda K, et al. Epidermal growth factor stimulates tyrosine phosphorylation of pig epidermal fibrous keratin. J Invest Dctmatol 1985: 84: 118-121. 31. Hennings H, Michael D, Cheng C, Steinert P Holbrook K, Yuspa S H. Calcium regulation of growth and differentiation of mouse epidermal cells in culture. Cell 1980: 19: 245-254. 32. Yuspa S H, Ben T, Hennings H, Lichiti U. Divergent responses in epidermal basal cells exposed to the tumor promoter 12-O-tetradecanoylphorbol-l 3-acetate. Cancer Res 1982:42: 2344-2349. 33. Yuspa S H, Ben T, Hennings H, Lichiti U. Phorbol ester tumor promoters induce epidermal transglutaminase activity. Biochem Biophys Res Commun 1980: 97: 700-708. 34. Inohara S, Tateishi H, Sagatni S. Diacylglycerol mimics phorbol ester induction of morphological changes in low Ca^+ regulated epidermal cells. J Dermatol (Tokyo) 1988: 15: 87-90.
35. Jeng A Y, Lichiti U, Strickland J E, Blumberg P M. Similar effects of phospholipase C and phorbol ester tumor promoters on primary mouse epidermal cells. Cancer Res 1985: 45: 5714-5721. 36. Isseroff R, Ziboh V A. Inohara S, Tang W, Pandey R. The biological significance of fatty acid turnover in keratinocyte proliferation and differentiation. In Bernstein 1 A, Hirone T, eds. Processes in Cutaneous Epidermal Differentiation. New York: Praeger. 1987: 49-68. 37. Isseroff R R. Stephens L E, Gross J L. Subcellular distribution of protein kinase C/photbol ester receptors in differentiating mouse keratinocytes. J Cell Physiol 1989: 141: 235-242. 38. Dlugosz A A, Yuspa S H. Staurosporine induces protein kinase C agonist effects and maturation of normal and ncopiastic mouse keratinocytes in vitro. Cancer Res 1991: 51:4677^684. 39. Kitajima Y, Inoue S, Nagao S, Nagata K. Yaoita H, Nozawa Y Biphasic effects of 12-O-tetradecanoylphorbol-l 3-acetate on the cell morphology of low calciumgrown human epidermal carcinoma cells: involvement of translocation and down regulation of protein kinase C. Cancer Res 1988: 48: 964-970. 40. Fournier A. Murray A W. Application of phorbol ester to mouse skin causes a rapid and sustained loss of protein kinase C. Nature 1987: 330: 767-769. 41. Hansen L A, Monteiro-Riviere N A, Smart R C. Differential down-regulation of epidermal protein kinase C by 12-O-tetradecanoylphorbol-13-acetate and diacylglycerol: association with epidermal hyperplasia and tumor promotion. Cancer Res 1990: 50: 5740-5745. 42. Leibersperger H, Gschwendt M, Gcrnold M, Marks F. Immunological demonstration of a calcium-unresponsive protein kinase C of the 5-type in different species and murine tissues, predominance in epidennis. J Biol Chem 1991: 266: 14778-14784. 43. Inohara S, Tateishi H, Takeda Y, Tanaka Y, Sagami S. Effects of protein kinase C activators on mouse skin in vivo. Arch Dermatol Res 1988: 280: 182-184. 44. Issandou M, Rozengurt E. Diacylglycerols, unlike phorbol esters do not induce homologous desensitization or down-regulation of protein kinase C in swiss 3T3 cells. Biochem Biophys Res Commun 1989: 163: 201-208. 45. Garte S J. Belman S. Tumor promoter uncouples P-adrenergic receptor from adcnyi cyclase in mouse epidermis. Nature 1980: 284: 171 173." 46. Silbcy D R, Nambi P, Peters J R, Lefkowitz R J. Phorbol esters promote P-adrenergic receptor phosphorylation and adenyl cyelase desensitization in duck erythrocytes. Biochem Biophys Res Comtnun 1984: 121: 973-979. 47. Furstenberger G, Marks F. Early prostaglandin H synthesis is an obligatory event in the induction of cell proliferation in mouse epidermis in vivo by the phorbol ester TPA. Biochem Biophys Res Commun 1980: 92: 749-756. 48. Ashendel C L, Boutwell R K. Prostaglandin E, and F,, levels in mou.se epidennis are increased by tumor-promoting phorbol esters. Biochem Biophys Res Cotnmun 1979: 90i 623-627. 49. Hammarstrom S, Lindgrcn J A. Marcel C. Duell E A, Anderson T F, Voorhees .1 J. Increased concentrations of non-esterified arachidonic acid. 12L-hydroxy-5.8,14eicostetraenoic acid, prostaglandin B, and prostaglandin F,, in the epidermis of psoriasis. Proc Natl Acad Sci USA 1975: 72: 5130-5134. 50. Voorhees J J. Leukolrienes and other lipoxygcnase products in pathogenesis and therapy of psoriasis and other dermatoses. Arch Dermatol 1983: 119: 541-547. 51. O'Brien T G, Simsiman R C, Boutwell R K. Induction of polyamine-biosynthetie enzymes in mouse epidermis by lunior-promoling agents. Cancer Res 1975: 35: 1662-1670.
217
Inohara 52. Marks F, Bertsch S, Furstenberger G. Ornithine decarboxylase activity, cell proliferation, and tumor promotion in mouse epidermis in vivo. Cancer Res 1979: 39: 4183-4188. 53. Russell D H, Combest W L, Duell E A, Stawiski M, Anderson T F, Voorhees J J. Glucocorticoid inhibits elevated polyamine biosynthesis in psoriasis. .1 Invest Dermatol 1978: 71: 177-181. 54. Yuspa S H, Ben T. Hennings H, Lichiti U. Phorbol ester tumor promoters induce epidermal transglutaminase activity. Biochem Biophys Res Commun 1980: 97: 700-708. 55. Esmann J, Cooper K D, Voorhees .1 J, Fisher G J. Membrane associated transglutaminase activity is increased in psoriatic versus normal epidermis. J Invest Dermatol 1988: 90: 556. 56. Lichiti U, Patterson E, Hennings H, Yuspa S H. Diflerential retinoic aeid inhibition of ornithine decarboxylase induction by 12-O-tetradecanoyl-phorbol-13-acetate and germicidal ultraviolet light. Cancer Res 1981: 41: 49-54. 57. Gschwendt M, Kittstein W, Horn F, Marks F. Cyclosporin A inhibits biological effects of tumor promoting phorbol esters. Biochem Biophys I^es Commun 1985: 126: 327-332. 58. Chida K, Hashiba H. Suda T, Kuroki T. Inhibition by la,25-hydroxyvitamin D, of epidermal ornithine decarboxylase caused by 12-O-tetradecanoyl-phorbol-13-acetate and tcleocidin B. Cancer Res 1984: 44: 1387-1391. 59. Horn F, Marks F, Fisher G J, Marcelo C L, Voorhees .1 J. Decreased protein kinase C activity in psoriatic versus normal epidermis. J Invest Dermatol 1987: 88: 220-222. 60. Inohara S, Tatsumi Y, Tanaka Y, Tateishi H, Sagami S. Immunohistological identification of protein kinase C isozymes in normal and psoriatic epidermis. Arch Dermatol Res 1988: 280: 454 455. 61. Young S, Rothbard J, Parker P J. A monoclonal antibody recognising the site of limited proteolysis of protein kinase C. Eur.l Biochem 1988: 173: 247-252. 62. Nishizuka Y. The family of protein kinase C for signal transduction. .lAMA 1989:262: 1826-1833. 63. Gentleman S, Martensen T M, Digiovanna J J, Chader G J. Protein tyrosine kinase and protein phosphotyrosine phosphatase in normal and psoriatic skin. Biochim Biophys Acta 1984: 798: 53-59. 64. Nanney L B, Stoscheck C M, Magid M, King L E. Altered ['"]epidermal growth factor binding and receptor distribution in psoriasis. J Invest Dermatol 1986: 86: 260-265. 65. Elder J T, Fisher G J, Lindquist P B. Overexpression of transforming growth factor a in psoriatic epidermis. Science 1989: 243: 81U8I4. 66. Pittelkow M R, Lindquist P B, Abraham R T, GravesDeal R, Derynck R, Coffey R J. Induction of transforming growth factor-a expression in human keratinocytes by phorbol ester. J Biol Chem 1989: 264: 5164-5171. 67. Inohara S. Signal transduction in normal and psoriatic epidermis. Int J Dermatol 1992: 31: 237 241. 68. Kumar R, Holian O. Retinoid effect on calcium, phospholipid-dependent protein kinase from mouse skin. 1986: 86: 316-320. 69. Walker R J, Lazzaro V A, Duggin G G, Horath J S, Tiller D J. Cyelosporin A inhibits protein kinase C activity: a contributing mechanism in the development of nephrotoxicity? Biochem Biophys Res Commun 1989: 160: 409-415. 70. von Ruecker A A, Rao G, Bidlingmainer F. Cyclosporin A inhibitis proteolytic cleavage and degradation of membrane-bound protein kina.se C in hepatocytes after stimulation by phorbol ester. Biochem Biophys Res Commun 1988: 151: 997-1003. 7L Lenardo M J, Baltimore D. NF-KB: a pleiotropic mediator of inducible and tissue-speeifie gene control. Cell 1989: 58: 227-229.
218
72. Ghosh S, Baltimore D. Activation in viiro of N F - K B by phosphorylation of its inhibitor IKB. Nature 1990: 344678-682. 73. Dvir A, Milner Y, Chomsky O, Gilon C, Grazit A, Levitzki A. The inhibition of EGF-dependent proliferation of keratinocytes by tyrophostin tyrosine kinase blockers J Cell Biol 1991: 113: 857-865. 74. Filvaroff E, Stern D F, Dotto G P. Tyrosine phosphorylation is an early and specific event involved in primary keratinocyte differentiation. Mol Cell Biol 1990- 101164-1173. 75. Force T, Kyriakis .1 M, Avruch .1. Bonventre J V. Endothelin, vasopressin. and angiotensin II enhance tyrosine phosphorylation by protein kinase C-dependent and -independent pathways in glomerular mesangial cells. J Biol Chem 1991: 266: 6650-6656. 76. CasiUas A, Hanekom C, Wiliams K, Katz R, Nel A E. Stimulation of B-cells via the membrane immunoglobulin receptor or with phorbol myristate I3-acetate induces tyrosine phosphorylation and activation of a 42-KDa microtuble-associated protein-2 kinase. J Biol Chem 1991: 266: 19088-19094. 77. Bishop J M. Molecular themes in oncogenesis. Cell 199164: 235-248. 78. Cantley L C, Auger K R, Carpenter C, et al. Oncogenes and signal transduction. Cell 1991: 64: 281-302. 79. Weiel J E, Ahn N G, Seger R. Krebs E G. Communication between protein tyrosine and protein serine/threonine phosphorylation. In Nishizuka Y, ed. The Biology and Medicine of Signal Transduction. New York: Raven Press, 1990: 182-195. 80. Thomas G. MAP kinase by any other name smells just as sweet. Cell 1992: 68: 3-6. 81. Freeman R S, Donoghue D J. Protein kinases and protooncogenes: biochemical regulators of the eukaryotic cell cycle. Biochemistry 1991: 30: 2293-2302. 82. Millar .1 B, Russell P The cdc25 M-phase inducer: an unconventional protein phosphatase. Cell 1992' 68' 407-4\0. 83. Nishibe S, Wahl M 1, Hernandez-Sotomayor S M T, Tonks N K, Rhee S G. Carpenter G. Increase of the catalytic activity of phospholipase C-y 1 by tyrosine phosphorylation. Seienee 1990: 250: 1253-1256. 84. Nanney L B, Yates R A, King L E. Modulation of epidermal growth factor receptors in psoriatic lesions during treatment with topical EGF. J Invest Dermatol 1992- 98' 296-301. 85. Gruppuso P A, Mikumo R, Brautigan D L. Braun L. Growth arrest induced by transforming growth factor pi is accompanied by protein phosphatase activation in human keratinocytes. J Biol Chem 1991: 266: 3444-3448. 86. Harvey J .1. An unidentified virus which causes the rapid production of tumours in mice. Nature 1964: 204: 1104-1105. 87. Kirstcn W H, Mayer L A. Morphologic responses to a murine erythroblastosis virus. .1 NatI Cancer lnst 1967' 39:311-319. 88. Shih C, Padhy L C, Murray M, Weinberg R A. Transforming genes of carcinomas and neuroblastomas introduced into mouse fibroblasts. Nature 1981: 290: 261-264. 89. Balmain A, Pragnell 1 B. Mouse skin carcinomas induced in vivo by chemical carcinogens have a transforming Harvey-ra.v oncogene. Nature 1983: 303: 72-74. 90. Barbacid M. ras GENES. Ann Rev Biochem 1987: 56: 779-827. 91. Chesa P G, Rettig W J, Melamed M R. Old L .1, Niman H L. Expression of p2r"" in normal and malignant lumian tissues: lack of association with proliferation and malignancy. Proc Natl Acad Sci USA 1987: 84: 3234-3238.
Signal transduction in skin 9 2 . Corominas M. Kainino H. Leon .1. Pellicer A. Oncogene activation in human benign tumors of the skin (keratoacanthomas): is HRAS involved in differentiation as well as proliferation? Proc Natl Acad Sci USA 1989: 86: 6372-6376. 9 3 . Kikuchi A, Amagai M. Hayakawa K, et al. Association of EGF receptor expression with proliferating cells and of ra.v p21 expression with differentiating cells in various skin tnmors. Br .1 Dermatol 1990: 123: 49-58. 9 4 . Inohara S. Kitano Y. Sagami S. Immunohistological localization of ra.v p21 in normal, hyperplastic and neoplastic epidermis. Int J Dermatol (in press). 95 Hall A Signal transduction through small GTPases - A tale of two GAPS. Cell 1992: 69: .389-391. 96. Kaplan D R, Morrison D K, Wong G, McCormick K, Williams L T. PDGF P-receptor stimulates tyrosine phosphorylation of GAP and association of GAP with a signaling complex. Cell 1990: 61: 125-133. 9 7 . Brown K. Buchmann A. Balmain A. Carcinogen-induced mutation in the mouse c-Ha-ra.« gene provide evidence of multiple pathways for tumor progression. Proc Natl Acad Sci USA 1990: 87: 538-542. 98. Weinberg I B. The role of protein kinase C in growth control and the concept of carcinogenesis as a progressive disorder in signal transduction. In Nishizuka Y, ed. The Bioloay and Medieine of Signal transduction. New York. Raven Press. 1990: 307-316. 9 9 . Suganuma M. Fujiki H. Suguri H. et al. Okadaie acid: an additional non-phorbol-12-tetradecanoate-13-acetatetype tumor promoter. Proc Natl Acad Sci USA 1988: 85: 1768-1771. 100. Cohen P, Holmes C F B, Tsukitani Y. Okadaie acid: a new probe for the study of cellular regulation. TIBS 1990: 15: 98-102. 101. Kopp R. Noeike B. Sauter G, Schildberg F W. Paumgartner G. Pfeiffer A. Altered protein kinase C activity in biopsies of human eolonic adenomas and earcinomas. Cancer Res 1991: 51: 205-210. 102. Hunter T. Cooperation between oncogenes. Cell 1991: 64: 249-270. 103. Uo S. Werth D K, Richert N D. Pastan I. Vinculin phosphorylation by the src kinase. .1 Biol Chem 1983: 258: 14626-14631. 104. Werth D K, Niedel .1 E, Pastan I. Vinculin: a cytoskeletal substrate of protein kinase C. .1 Biol Chem 1983: 258: 11423-11426. 105. Jaken S, Leach K. Klauck T. Association of type 3 protein kinase C with focal contacts in rat embryo llbioblasts. .1 Cell Biol 1989: 109: 697 704. 106. Tsukitani S, Oishi K, Akiyama T, Yamanishi Y, Yaniamoto T. Tsukitani S. Speeific proto-oncogenic tyrosine kinases of src family are enriched in cell-to-ccll adherens junctions where the level of tyrosine phosphorylation is elevated. .1 Cell Biol 1991: 113: 867-879. 107. O'Keefe E J. Briggaman R A, Herman B. Calcium-induced assembly of adherens junctions in keratinocytes. .1 Cell Biol 1987:' 105: 807-817. 108. Rosen A, Keenan K F, Thelen M, Narin A C. Aderem A. Activation of protein kinase C results in the displaeement of ils niyriostoylaled. alanine-rich substrate from punctates in macrophage filopodia. .1 Fxp Med 1990: 172: 1211-1215. 109. Thelen M. Rosen A. Narin A C, Aderem A. Regulation by phosphorylation of reversible association of a myristoylaled protein kinase C substi'ate with llie plasma membrane. Nature 1991: 351: 320 322. 110. Hartwig J H, Thelen M. Rosen A, .lanmey P A, Nairn A C. Aderem A. MARCKS is an actin filament crosslinking protein regulated by protein kinase C and calcium-calmodtiljn. Nature 1992! 356: 618-622.
111. Sheu H-M. Kitajima Y. Yaoita H. Involvement of protein kinase C in translocation of desmoplakin from cytosol to plasma membrane during desmosome formation in human squamous cell carcinoma cells grown in low to normal calcium concentration. Exp Cell Res 1989: 185: 176-190. 112. Inohara S. Tatsumi Y. Cho H. Tanaka Y, Sagami S. Actin filament and desmosome formation in cultured human keratinocytes. Arch Dermatol Res 1990: 282: 210-212. 113. Inohara S. Tatsumi Y. Tanaka Y. Sagami S. Immunohistochemical localization of desmosomal and cytoskeletal proteins in the epidermis of healthy individuals and patients with Hailey-Hailey's di.sea.se. Aeta Derm Venereol (Stockh) 1990: 70: 239-241. 114. Eisinger M, Mark O. Selective proliferation of normal human melanocytes in vitro in the presence of phorbol ester and cholera toxin. Proc Natl Acad Sci USA 1982: 79: 2018-2022. 115. Halaban R, Langdon R. Birchall N. et al. Basic fibroblast growth factor from human keratinoeytes is a natural mitogen for melanocytes. .1 Cell Biol 1988: 107: 1611-1619. 116. Yaar M, Gilchrest BA. Human melanocyte growth and differentiation: a decade of new data. .1 Invest Dermatol 1991: 97: 611-617. 117. Gordon P R, Gilchrest B A. Human melanogenesis is stimulated by diaeylglyeerol. .1 Invest Dermatol 1989: 93: 700-702. 118. Friedmann P S, Wren F E, Matthews .1 N S. Ultraviolet stimulated melanogenesis by human melanocytes is augmented by diacylglycerol but not TPA. .1 Cell Physiol 1990: 142: 334-.341. 119. Brooks G, Wilson R E. Dooley T P. Gross M W. Hart 1 R. Protein kinase C downregulation, and not transient activation, correlates with melanocyte growth. Cancer Res 1991: 51: 3281-3288. 120. Iwamoto T. Takahashi M, Ito M, et al. Aberrant melanogenesis and melanocytic tumor development in transgenic mice that carry a metallothionein/rrv fusion gene. EMBO.1 1991: 10: 3167-3175. ' - ' • Halliday G M. Odling K A, Ruby .1 C, Muller H K. Suppressor cell activation and enhanced skin allograft survival after tumor promoter but not initiator induced depletion of cutaneous Langerhans cells. .1 Invest Dermatol 1988: 90: 293-297. Czernielewski .1 M. Demarchez M. Further evidence for 122. the self-reproducing capacity of Langerhans cells in human skin. .1 Invest Dermatol 1987: 88: 17-20. Koyama Y. Hachiya T. Hagiwara M. et al. Expression of 123. protein kinase C isozynie in epidermal Langerhans cells of the mouse. .1 Invest' Dermatol 1990: 94: 677-680. Koyama Y. Eukaya Y, Ueda H, et al. Expression of pro124. tein kinase C isozyme in human Langerhans' cells. Acta Derm Venereol (St'ockh) 1990: 70: 502-505. Moore G P M. Panaretto B A. Robertson D .1. Effects of 125. epidermal growth factor on hair growth in the mouse. Endocrinology 1981: 88: 293-299. Philport M P. Green M R, Kealey T. Human hair growth 126. /;, vitro. J Cell Sci 1990: 97: 46.3^71. Green M R, Couehman .1 R. Distribution and number of 127. epidermal growth factor receptors in rat tissues during embryonic development, hair formation, and the adult hair growth cycle. .1 Invest Dermatol 1984: 83: 118-123. Nanney L B. Magid M, Stoscheck M. King L E. Compari128. son of epidermal growth factor binding and receptor distribution in normal human epidermis and epidermal appandages. .1 Invest Dermatol 1984: 83: 385-393. 129. Ogawa H, Hallori M. Regulation mechanistiis of hair growth. In: Seiji M. Bernstein I A. eds. Abnormal Epidermal Differentiation. Tokyo: University of Tokyo Press, 198.3: 159-170.
219
Inohara 130. Kono T, Fukuda M, Ishii M, et al. Detection of ornithine decarboxylase gene expression in 12-O-tetradecanoylphorbol-13-acetate-treated mouse skin using in situ hybridization. Acta Derm Venereol (Stockh) 1991: 71: 104-107. 131. Priestley G C, Adams L W. Hyperactivity of fibroblasts cultured from psoriatic skin, I. Faster proliferation and effect of serum withdrawal. Br .1 Dermatol 1983: 109: 149-156. 132. Priestley G C, Adams L W. Mitogenic effeets of sera from normal and psoriatic subjects on human fibroblasts. Arch Dermatol Res 1985: 277:' 13-15. 133. Brion D E, Raynaud E, Plet A, Laurent P. Leduc B, Anderson W. Deficiency of cyclic AMP-dependent protein kinase in human psoriasis. Proc Natl Acad Sci USA 1986: 83: 5722-5726. 134. Nagao S, Seishima M, Mori S, Nozawa Y. Increased protein kinase C activity in fibroblast membranes from psoriatie patients. J Invest Dermatol 1988: 90: 406-408. 135. Raynaud E, Evain-Brion D. Protein kinase C activity in normal and psoriatic cells: cultures of fibroblasts and lymphocytes. Br .1 Dermatol 1991: 124: 542-546. 136. Davison P M, Bensch K G, Kara.sek M A. Isolation and growth of endothelial cells from the microvessels of the newborn human foreskin in cell culture. J Invest Dermatol 1980: 75: 316-321. 137. Karasek M A. Microvascular endothelial cell culture. J Invest Dermatol 1989: 93: 3.3-38. 138. Karasek M A. Mechanisms of angiogenesis in normal and diseased skin. Int J Dermatol 1991: 30: 831-836. 139. Davison P M, Karasek M A. Human dermal microvascular endothelial cells in vitro: effects of cyclic AMP on cellular morphology and proliferation rate. .1 Cell Physiol 1981: 106: 253-258. 140. Tuder R M, Karasek M A, Bensch K G. Cyclic adenosine monophosphate levels and the function of skin microvascular endothelial cells. J Cell Physiol 1990: 142: 272-283. 141. Hall A. The cellular functios of .small GTP-binding proteins. Science 1990: 249: 635-640.
220
142. Kikuchi A, Yamashita T, Kawata M, et al. Purification and characterization of a novel GTP-binding protein with a molecular weight of 24,000 from bovine brain membranes. J Biol Chem 1988: 263: 2897-2904. 143. Matsui Y, Kikuchi A. Kondo J, Hishida T, Teranishi Y, Takai Y. Nucleotide and deduced amino acid sequences of a GTP-binding protein family with molecular weight of 25,000 from bovine brain. J Biol Chem 1988- ''6311071-11074. 144. Mizoguchi A, Kim S, Ueda T, Takai Y. Tissue distribution of ,s7»g p25A, a ra.v p21-like GTP-binding protein, studied by use of a specific monoclonal antibody. Biochem Biophys Res Commun 1989: 162: 1438-1445. 145. Inohara S, Tanaka Y, Kitano Y, et al. Immunohistological localization of smg p25A. a ras p21-like guanosine 5'triphosphate (GTP)-binding protein in human skin. Arch Dermatol Res 1992: 284: 109-110. 146. Morita M, Yamagata M, Inohara S, Sagami S. Flow cytometric analysis of protein kinase C in lymph node cells during the induction phase of contact hypersensitivity reaction. J Dermatol (Tokyo) 1989: 16: 352-354. 147. Amon U, Dietz K R. Protein kinase C: a target for antiinfiammatory therapy? Arch Dermatol Res 1992' 7848-10. 148. Hanks S K, Quinn A M, Hunter T. The protein kinase family: eonserved features and deduced phylogeny of tbe catalytic domains. Science 1988: 241: 42-52. 149. Osada S, Mizuno K, Saido T C, et al. A phorbol ester receptor/protein kinase C, nPKCii, a new member of the protein kinase C family predominantly expressed in lung and skin. J Biol Chem 1990: 265: 22434-22440. 150. Gherzi R, Sparatore B, Patrone M, Sciutto A, Briata P. Protein kinase C mRNA levels and activity in reconstituted normal human epidermis: relationships to cell differentiation. Biochem Biophys Res Commun 199"'- 184283-291.
Esp ncrmalol IW:: I' 2117 220 Primed ill Dfilimirk . Ail riyiiis n'scni'ii
1992
ISSN
Review Article
Studies and perspectives of signal transduction in the skin Inohara S. Studies and perspectives of signal transduction in the skin. Exp Dermatol 1992: 1: 207-220. iQ Munksgaard, 1992 Abstract: Tumor-promoting phorbol ester and epidermal growth factor (EGF) exert marked intluences on the proliferation and differentiation of keratinocytes. These two agents bring their physiological functions into play via protein kinase C (PKC) activation (and/or down regulation) and protein tyrosine kinase, respectively. In this paper, the present situation in the studies on the signal transduction of keratinocytes centering around these two kinases is discussed. An outline of studies on signal transduction of cells other than keratinocytes in the skin is also given.
Introduction Studies on signal transduction made explosive progress centering around protein phosphorylation in 1980s. In the domain of dermatology, too, many new findings have been reported. In this paper I give an outline of studies in dermatology, together with the results of studies in basic science, and present the outlook for the future. To begin with, a history of studies on signal transduction and an outline of modes of signal transduction which have been established up to the present (Fig. 1) will be mentioned. The first step in studies in this field was the discovery of cAMP by Sutherland (1). That is, the tnechanism has been made clear whereby sigtials frotn outside cells such as hormones combine with the receptor of cells to increase cAMP in cells. In 1968, the group of Krebs discovered cAMP-dependent protein kinase (Protein kinase A, PKA) (1). Studies made thereafter revealed that the intracellular action of cAMP is exerted via activation of PKA. However, it has also been discovered that many extracellular signals do not go through the route of the cAMP-PKA system. And it has long been known that many of those signals degrade inositol phospholipids (PI) of cell tnembranes (2, 3). The physiological meaning of this retrained unknown for a long time. In 1980s, however, it was found that diacylglycerol, a metabolite of PI, activates protein kinase C (PKC) and that inositol triphosphate (IP^), the another metabolite of PI, mobilizes intracellular Cir^ (4-6) (Fig. 1). Furthei tnore, it has also been shown thai
Shinichi Inohara Department ol Dermatology, Hyogo College of Medicine, Hyogo, Japan
Key words: skin - protein kinase C - protein tyrosine kinase - phosphorylation Shinichi Inohara. M.D., Department of Dermatology. Hyogo College of Medicine. Nishinomiya, Hyogo 663. Japan Accepted for publication 15 January 1993
Ca-^ cotnbine with calmodulin (CDR) to activate Ca'+ and CDR-dependent protein kinase. Therefore it has been made clear that these kinases are activated by metabolites of PI to have information ttansmitted into the inside of cells (Fig. 1). The signal transduction composed mainly of these kinases was at first thought to be concerned with the short-tertn reactions of hormones and neurotransmitters. Recently, however, it has becotne clear that these kinases are concerned with long-term reactions, such as proliferation, differentiation and oncogenesis as well and this has become particularly evident in PKC. ln 1982 it was discovered that tumor-promoting phorbol esters activate PKC directly without taking part in the degradation of PI (7). Furthertnore, studies conducted subsequently have tevealed that PKC is itself the receptor of phorbol esters (8). Since phorbol esters exert marked effects on proliferation, differentiation and oncogenesis, there is a strong possibility that PKC is concerned with such long-lertn reactions. Further, it has also been confirmed that various growth factors such as platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) have PI degradating ability (9). Accordingly, PKC is thought to serve as the focus of action for those growth factors. ^ PKA, PKC, Ca=+ and CDR-dependent PK are protein kinases that phosphorylate serine and threonine of protein, i.e. are serine-threonine kinases. In the 1980s, the presence of protein kinase that phosphorylates tyrosirie, that is protein tyrosine kinase (PTK), was demonsttated (10, 11). To begin 207
Inohara with, it was proven by the group of Hunter that p60''""', a product of v-.src which was an oncogene of Rous sarcoma virus, had PTK activity (10). Furthermoi"e, it became clear that many of the other oticogene products also had PTK activity (11) and that the receptors for various growth factors also had PTK activity (11, 12). Therefore, PTK might be an enzyme that is closely related to proliferation. Phorbol ester being a tumor promoter in mouse epidermis exerts marked effects on proliferation, differentiation and tumorigenesis of the epidermis (13). Epidermal growth factor (EGF) whose receptor has PTK activity also exerts marked effects on proliferation and differentiation in the epidermis (14). Therefore, it is highly possible that serinethreonine kinases, mainly PKC and PTK, play important roles in proliferation, differentiation and tumorigenesis of keratinocytes. Now mention will be made of studies mainly on signal transduction of keratinocytes and also of cells other than keratinocytes in the skin. (Fig. 1 illustrates main route of signal transduction to be described later). I. Signal transduction in keratinocytes 1) Proliferalicm atul differentiation i) cAMP-PKA system: What first attracted attention in the studies on signal transduction in keratinocytes was a study of the cAMP-PKA system. cAMP has attracted attention in dermatology since Voorhees' report that cAMP is decreased in psoriatic epidermis compared with normal epidermis (15). At that time, cAMP was thought to act in suppressing proliferation; so, hyperproliferation of
Hormone etc
I'horbol ester j
PKC
i, ®1)rotein (Ser, Thr)
C a " CDR d e p t .
Drotein (Ser. Thr)
fos.
(J>protein CSer. Tlir)
Tt \
IPTK
(J^protein (Tyr)
jun
NUCLEUS
Figure !. Authentic scenario of signal transduction. G protein: GTP-bindiiig protein, PI: inosilol plio.spholipids, DG: diacylglycerol, IP': inositol triphosphale. PKA: protein kinase A, PKC: protein kinase C. PTK: protein lyro.sine kina.se. C1815-1818. 2. Flokin M R, Hokin L E. Enzyme secretion and the incorporation of '-P into phospholipids of pancreatic slices J Biol Chem 1953: 203: 967-977. 3. Michell R H. Inositol phospholipids and cell surface receptor function. Biochim Biophys Acta 1975: 415: 81-147. 4. Kikkawa U, Takai Y, Minakuchi R, Inohara S, Nishizuka Y. Calcium-activated, phospholipid-depcndent protein kinase from rat brain, subecllular distribution, purification, and properties. J Biol Chem I98T- '>5713341-13348. 5. Nishizuka Y. The role of protein kinase C in cell surface signal transduction and tumor promotion Nature 1984308: 693-698. 6. Berridge M J, Irvine R F. Inositol triphosphate, a novel second messenger in cellular signal transduction Nature 1984: 312: 315-324. 7. Castagna M, Takai Y, Kaibuchi K, Sano K, Kikkawa U, Nishizuka Y. Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol ester. J Biol Chem 1982: 257: 7847-7851. 8. Nishizuka Y Studies and perspectives of protein kinase C. Science 1986: 233: 305-312. 9. Berridge M J. Inositol lipid and cell pioliferation. Biochim Biophys Aeta 1987: 907: 33-45. 10. Hunter T, Scfton B W. Transforming gene product of rous sarcoma virus phosphorylates tyrosine. Proc NatI Acad Sci USA 1980: 77: 1311-1315. 11. Hunter T. Cooper J A. Protcin-tyrosine kinases. Ann Rev Biochem 1985: 54: 897-930. 12. Ushito H, Cohen S. Identification of phosphotyrosine as a product of epidermal growth factor-activated protein kinase in A-431 cell membranes. J Biol Chem 1980- "'558363-8365. 13. Yuspa S H. Tumor promotion in epidermal cells in culture. In Slaga T J, ed. Mechanism of Tumor Promotion, vol in Tumor Promotion and Careinogenesis in Vitro Boca Raton, Fla: CRC Press, 1984: 1-11. 14. Yates R A, Nanney L B, Gates R E, King L E. Epidermal growth factor and related growth factors. Int I Dermatol 1991: 687-694.
Signal transduction in skin 1 5. Voorhees J J, Duell E A. Psoriasis as a possible defect of the adenyl cyclasc-cyclic AMP cascade. Arch Dermatol 1971: 104: 352-358. 16. Green H. Cyclic AMP in relation to proliferation of the epidermal cell: a new view. Cell 1978: 15: 801-811. 17. Okada N, Kitano Y, Ichihara K. Effects of cholera toxin on proliferation of cultured human keratinocytes in relation to intracellular cyclic AMP levels. .1 Invest Dermatol 1982: 79: 42^7. 18. Adachi K. lizuka H, Halprin K M, Levine V. Epidermal cyclic AMP is not decrea.sed in psoriatic lesions. J Invest Dermatol 1980: 74: 74-76. 19. Inohara S, Sagami S. Phosphorylation of epidermal keratin proteins by cyclic AMP-dependent protein kinase. Arch Dermatol Res 1983: 275: 417^18. 20. Ikai K, McGuire J. Phosphorylation of keratin polypeptidcs. Biochim Biophys Acta 1983: 760: 371-376. 2 1 . Yoshikawa K, Takeda J, Ncmoto O, Uo T Halprin K M, Adachi K. Phosphorylation of pig epidermal soluble protein by endogeneous cAMP-dcpendent protein kinase. J Invest Dermatol 1983: 80: 108-111. 22. Edinger F M, Penn A. Tumor promoter-stimulated protein phosphorylation in mouse epidermis is inhibited by bromophenacyl bromide. J Invest Dermatol 1985: 84: 413-416. 23. Koizumi H, Aoyagi T, Ohkawara A. Phosphorylation of soluble pig epidermal proteins by endogeneous calciumactivated, phospholipid-dependent protein kinase. Arch Dermatol Res 1986: 279: 95-99. 24. Gschwendt M, Kittstein W, Marks F. A novel type of pborbol ester-dependent protein phosphorylation in the particulate fraction of mouse epidertnis. Biochem Biophys Res Commun 1986: 137: 766-114. 25. Chida K, Tsunenaga M, Kasahara K, Kohno Y, Kuroki T. Regulation of creatinine phosphokinase B activity by protein kinase C. Biochem Biophys Res Commun 1990: 173: 346-350. 26. Smith B M. Colburn N H. Protein kinase C and its substrates in tumor promoter-sensitive and -resistant cells. J Biol Chem 1988: 263: 6424-6431. 27. Takahashi M, Tezuka T, Towatari T, Katunuma N. Identification of hematoxylin-stainable protein in epidermal keratohyalin granule as phosphorylated cystatin a by protein kinase C. FEBS LeU 1991: 287: 178-180. 28. Chakravarty R. Rong X, Rice R H. Phorbol estet-stitnulated phosphorylation of keratinocyte transglutaminase in the membrane anchorage region. Biochem J 1990: 271: 25-30. 29. Kasahara K. Chida K, Tsunenaga M, Kohno Y, lkuta T Kuroki T Identification of lamin B, as a substrate of protein kinase C in BALB/MK-2 mouse keratinocytes. J Biol Chem 1991: 266: 20018-20023. 30. Aoyagi T, Suya H, Umeda K, et al. Epidermal growth factor stimulates tyrosine phosphorylation of pig epidermal fibrous keratin. J Invest Dctmatol 1985: 84: 118-121. 31. Hennings H, Michael D, Cheng C, Steinert P Holbrook K, Yuspa S H. Calcium regulation of growth and differentiation of mouse epidermal cells in culture. Cell 1980: 19: 245-254. 32. Yuspa S H, Ben T, Hennings H, Lichiti U. Divergent responses in epidermal basal cells exposed to the tumor promoter 12-O-tetradecanoylphorbol-l 3-acetate. Cancer Res 1982:42: 2344-2349. 33. Yuspa S H, Ben T, Hennings H, Lichiti U. Phorbol ester tumor promoters induce epidermal transglutaminase activity. Biochem Biophys Res Commun 1980: 97: 700-708. 34. Inohara S, Tateishi H, Sagatni S. Diacylglycerol mimics phorbol ester induction of morphological changes in low Ca^+ regulated epidermal cells. J Dermatol (Tokyo) 1988: 15: 87-90.
35. Jeng A Y, Lichiti U, Strickland J E, Blumberg P M. Similar effects of phospholipase C and phorbol ester tumor promoters on primary mouse epidermal cells. Cancer Res 1985: 45: 5714-5721. 36. Isseroff R, Ziboh V A. Inohara S, Tang W, Pandey R. The biological significance of fatty acid turnover in keratinocyte proliferation and differentiation. In Bernstein 1 A, Hirone T, eds. Processes in Cutaneous Epidermal Differentiation. New York: Praeger. 1987: 49-68. 37. Isseroff R R. Stephens L E, Gross J L. Subcellular distribution of protein kinase C/photbol ester receptors in differentiating mouse keratinocytes. J Cell Physiol 1989: 141: 235-242. 38. Dlugosz A A, Yuspa S H. Staurosporine induces protein kinase C agonist effects and maturation of normal and ncopiastic mouse keratinocytes in vitro. Cancer Res 1991: 51:4677^684. 39. Kitajima Y, Inoue S, Nagao S, Nagata K. Yaoita H, Nozawa Y Biphasic effects of 12-O-tetradecanoylphorbol-l 3-acetate on the cell morphology of low calciumgrown human epidermal carcinoma cells: involvement of translocation and down regulation of protein kinase C. Cancer Res 1988: 48: 964-970. 40. Fournier A. Murray A W. Application of phorbol ester to mouse skin causes a rapid and sustained loss of protein kinase C. Nature 1987: 330: 767-769. 41. Hansen L A, Monteiro-Riviere N A, Smart R C. Differential down-regulation of epidermal protein kinase C by 12-O-tetradecanoylphorbol-13-acetate and diacylglycerol: association with epidermal hyperplasia and tumor promotion. Cancer Res 1990: 50: 5740-5745. 42. Leibersperger H, Gschwendt M, Gcrnold M, Marks F. Immunological demonstration of a calcium-unresponsive protein kinase C of the 5-type in different species and murine tissues, predominance in epidennis. J Biol Chem 1991: 266: 14778-14784. 43. Inohara S, Tateishi H, Takeda Y, Tanaka Y, Sagami S. Effects of protein kinase C activators on mouse skin in vivo. Arch Dermatol Res 1988: 280: 182-184. 44. Issandou M, Rozengurt E. Diacylglycerols, unlike phorbol esters do not induce homologous desensitization or down-regulation of protein kinase C in swiss 3T3 cells. Biochem Biophys Res Commun 1989: 163: 201-208. 45. Garte S J. Belman S. Tumor promoter uncouples P-adrenergic receptor from adcnyi cyclase in mouse epidermis. Nature 1980: 284: 171 173." 46. Silbcy D R, Nambi P, Peters J R, Lefkowitz R J. Phorbol esters promote P-adrenergic receptor phosphorylation and adenyl cyelase desensitization in duck erythrocytes. Biochem Biophys Res Comtnun 1984: 121: 973-979. 47. Furstenberger G, Marks F. Early prostaglandin H synthesis is an obligatory event in the induction of cell proliferation in mouse epidermis in vivo by the phorbol ester TPA. Biochem Biophys Res Commun 1980: 92: 749-756. 48. Ashendel C L, Boutwell R K. Prostaglandin E, and F,, levels in mou.se epidennis are increased by tumor-promoting phorbol esters. Biochem Biophys Res Cotnmun 1979: 90i 623-627. 49. Hammarstrom S, Lindgrcn J A. Marcel C. Duell E A, Anderson T F, Voorhees .1 J. Increased concentrations of non-esterified arachidonic acid. 12L-hydroxy-5.8,14eicostetraenoic acid, prostaglandin B, and prostaglandin F,, in the epidermis of psoriasis. Proc Natl Acad Sci USA 1975: 72: 5130-5134. 50. Voorhees J J. Leukolrienes and other lipoxygcnase products in pathogenesis and therapy of psoriasis and other dermatoses. Arch Dermatol 1983: 119: 541-547. 51. O'Brien T G, Simsiman R C, Boutwell R K. Induction of polyamine-biosynthetie enzymes in mouse epidermis by lunior-promoling agents. Cancer Res 1975: 35: 1662-1670.
217
Inohara 52. Marks F, Bertsch S, Furstenberger G. Ornithine decarboxylase activity, cell proliferation, and tumor promotion in mouse epidermis in vivo. Cancer Res 1979: 39: 4183-4188. 53. Russell D H, Combest W L, Duell E A, Stawiski M, Anderson T F, Voorhees J J. Glucocorticoid inhibits elevated polyamine biosynthesis in psoriasis. .1 Invest Dermatol 1978: 71: 177-181. 54. Yuspa S H, Ben T. Hennings H, Lichiti U. Phorbol ester tumor promoters induce epidermal transglutaminase activity. Biochem Biophys Res Commun 1980: 97: 700-708. 55. Esmann J, Cooper K D, Voorhees .1 J, Fisher G J. Membrane associated transglutaminase activity is increased in psoriatic versus normal epidermis. J Invest Dermatol 1988: 90: 556. 56. Lichiti U, Patterson E, Hennings H, Yuspa S H. Diflerential retinoic aeid inhibition of ornithine decarboxylase induction by 12-O-tetradecanoyl-phorbol-13-acetate and germicidal ultraviolet light. Cancer Res 1981: 41: 49-54. 57. Gschwendt M, Kittstein W, Horn F, Marks F. Cyclosporin A inhibits biological effects of tumor promoting phorbol esters. Biochem Biophys I^es Commun 1985: 126: 327-332. 58. Chida K, Hashiba H. Suda T, Kuroki T. Inhibition by la,25-hydroxyvitamin D, of epidermal ornithine decarboxylase caused by 12-O-tetradecanoyl-phorbol-13-acetate and tcleocidin B. Cancer Res 1984: 44: 1387-1391. 59. Horn F, Marks F, Fisher G J, Marcelo C L, Voorhees .1 J. Decreased protein kinase C activity in psoriatic versus normal epidermis. J Invest Dermatol 1987: 88: 220-222. 60. Inohara S, Tatsumi Y, Tanaka Y, Tateishi H, Sagami S. Immunohistological identification of protein kinase C isozymes in normal and psoriatic epidermis. Arch Dermatol Res 1988: 280: 454 455. 61. Young S, Rothbard J, Parker P J. A monoclonal antibody recognising the site of limited proteolysis of protein kinase C. Eur.l Biochem 1988: 173: 247-252. 62. Nishizuka Y. The family of protein kinase C for signal transduction. .lAMA 1989:262: 1826-1833. 63. Gentleman S, Martensen T M, Digiovanna J J, Chader G J. Protein tyrosine kinase and protein phosphotyrosine phosphatase in normal and psoriatic skin. Biochim Biophys Acta 1984: 798: 53-59. 64. Nanney L B, Stoscheck C M, Magid M, King L E. Altered ['"]epidermal growth factor binding and receptor distribution in psoriasis. J Invest Dermatol 1986: 86: 260-265. 65. Elder J T, Fisher G J, Lindquist P B. Overexpression of transforming growth factor a in psoriatic epidermis. Science 1989: 243: 81U8I4. 66. Pittelkow M R, Lindquist P B, Abraham R T, GravesDeal R, Derynck R, Coffey R J. Induction of transforming growth factor-a expression in human keratinocytes by phorbol ester. J Biol Chem 1989: 264: 5164-5171. 67. Inohara S. Signal transduction in normal and psoriatic epidermis. Int J Dermatol 1992: 31: 237 241. 68. Kumar R, Holian O. Retinoid effect on calcium, phospholipid-dependent protein kinase from mouse skin. 1986: 86: 316-320. 69. Walker R J, Lazzaro V A, Duggin G G, Horath J S, Tiller D J. Cyelosporin A inhibits protein kinase C activity: a contributing mechanism in the development of nephrotoxicity? Biochem Biophys Res Commun 1989: 160: 409-415. 70. von Ruecker A A, Rao G, Bidlingmainer F. Cyclosporin A inhibitis proteolytic cleavage and degradation of membrane-bound protein kina.se C in hepatocytes after stimulation by phorbol ester. Biochem Biophys Res Commun 1988: 151: 997-1003. 7L Lenardo M J, Baltimore D. NF-KB: a pleiotropic mediator of inducible and tissue-speeifie gene control. Cell 1989: 58: 227-229.
218
72. Ghosh S, Baltimore D. Activation in viiro of N F - K B by phosphorylation of its inhibitor IKB. Nature 1990: 344678-682. 73. Dvir A, Milner Y, Chomsky O, Gilon C, Grazit A, Levitzki A. The inhibition of EGF-dependent proliferation of keratinocytes by tyrophostin tyrosine kinase blockers J Cell Biol 1991: 113: 857-865. 74. Filvaroff E, Stern D F, Dotto G P. Tyrosine phosphorylation is an early and specific event involved in primary keratinocyte differentiation. Mol Cell Biol 1990- 101164-1173. 75. Force T, Kyriakis .1 M, Avruch .1. Bonventre J V. Endothelin, vasopressin. and angiotensin II enhance tyrosine phosphorylation by protein kinase C-dependent and -independent pathways in glomerular mesangial cells. J Biol Chem 1991: 266: 6650-6656. 76. CasiUas A, Hanekom C, Wiliams K, Katz R, Nel A E. Stimulation of B-cells via the membrane immunoglobulin receptor or with phorbol myristate I3-acetate induces tyrosine phosphorylation and activation of a 42-KDa microtuble-associated protein-2 kinase. J Biol Chem 1991: 266: 19088-19094. 77. Bishop J M. Molecular themes in oncogenesis. Cell 199164: 235-248. 78. Cantley L C, Auger K R, Carpenter C, et al. Oncogenes and signal transduction. Cell 1991: 64: 281-302. 79. Weiel J E, Ahn N G, Seger R. Krebs E G. Communication between protein tyrosine and protein serine/threonine phosphorylation. In Nishizuka Y, ed. The Biology and Medicine of Signal Transduction. New York: Raven Press, 1990: 182-195. 80. Thomas G. MAP kinase by any other name smells just as sweet. Cell 1992: 68: 3-6. 81. Freeman R S, Donoghue D J. Protein kinases and protooncogenes: biochemical regulators of the eukaryotic cell cycle. Biochemistry 1991: 30: 2293-2302. 82. Millar .1 B, Russell P The cdc25 M-phase inducer: an unconventional protein phosphatase. Cell 1992' 68' 407-4\0. 83. Nishibe S, Wahl M 1, Hernandez-Sotomayor S M T, Tonks N K, Rhee S G. Carpenter G. Increase of the catalytic activity of phospholipase C-y 1 by tyrosine phosphorylation. Seienee 1990: 250: 1253-1256. 84. Nanney L B, Yates R A, King L E. Modulation of epidermal growth factor receptors in psoriatic lesions during treatment with topical EGF. J Invest Dermatol 1992- 98' 296-301. 85. Gruppuso P A, Mikumo R, Brautigan D L. Braun L. Growth arrest induced by transforming growth factor pi is accompanied by protein phosphatase activation in human keratinocytes. J Biol Chem 1991: 266: 3444-3448. 86. Harvey J .1. An unidentified virus which causes the rapid production of tumours in mice. Nature 1964: 204: 1104-1105. 87. Kirstcn W H, Mayer L A. Morphologic responses to a murine erythroblastosis virus. .1 NatI Cancer lnst 1967' 39:311-319. 88. Shih C, Padhy L C, Murray M, Weinberg R A. Transforming genes of carcinomas and neuroblastomas introduced into mouse fibroblasts. Nature 1981: 290: 261-264. 89. Balmain A, Pragnell 1 B. Mouse skin carcinomas induced in vivo by chemical carcinogens have a transforming Harvey-ra.v oncogene. Nature 1983: 303: 72-74. 90. Barbacid M. ras GENES. Ann Rev Biochem 1987: 56: 779-827. 91. Chesa P G, Rettig W J, Melamed M R. Old L .1, Niman H L. Expression of p2r"" in normal and malignant lumian tissues: lack of association with proliferation and malignancy. Proc Natl Acad Sci USA 1987: 84: 3234-3238.
Signal transduction in skin 9 2 . Corominas M. Kainino H. Leon .1. Pellicer A. Oncogene activation in human benign tumors of the skin (keratoacanthomas): is HRAS involved in differentiation as well as proliferation? Proc Natl Acad Sci USA 1989: 86: 6372-6376. 9 3 . Kikuchi A, Amagai M. Hayakawa K, et al. Association of EGF receptor expression with proliferating cells and of ra.v p21 expression with differentiating cells in various skin tnmors. Br .1 Dermatol 1990: 123: 49-58. 9 4 . Inohara S. Kitano Y. Sagami S. Immunohistological localization of ra.v p21 in normal, hyperplastic and neoplastic epidermis. Int J Dermatol (in press). 95 Hall A Signal transduction through small GTPases - A tale of two GAPS. Cell 1992: 69: .389-391. 96. Kaplan D R, Morrison D K, Wong G, McCormick K, Williams L T. PDGF P-receptor stimulates tyrosine phosphorylation of GAP and association of GAP with a signaling complex. Cell 1990: 61: 125-133. 9 7 . Brown K. Buchmann A. Balmain A. Carcinogen-induced mutation in the mouse c-Ha-ra.« gene provide evidence of multiple pathways for tumor progression. Proc Natl Acad Sci USA 1990: 87: 538-542. 98. Weinberg I B. The role of protein kinase C in growth control and the concept of carcinogenesis as a progressive disorder in signal transduction. In Nishizuka Y, ed. The Bioloay and Medieine of Signal transduction. New York. Raven Press. 1990: 307-316. 9 9 . Suganuma M. Fujiki H. Suguri H. et al. Okadaie acid: an additional non-phorbol-12-tetradecanoate-13-acetatetype tumor promoter. Proc Natl Acad Sci USA 1988: 85: 1768-1771. 100. Cohen P, Holmes C F B, Tsukitani Y. Okadaie acid: a new probe for the study of cellular regulation. TIBS 1990: 15: 98-102. 101. Kopp R. Noeike B. Sauter G, Schildberg F W. Paumgartner G. Pfeiffer A. Altered protein kinase C activity in biopsies of human eolonic adenomas and earcinomas. Cancer Res 1991: 51: 205-210. 102. Hunter T. Cooperation between oncogenes. Cell 1991: 64: 249-270. 103. Uo S. Werth D K, Richert N D. Pastan I. Vinculin phosphorylation by the src kinase. .1 Biol Chem 1983: 258: 14626-14631. 104. Werth D K, Niedel .1 E, Pastan I. Vinculin: a cytoskeletal substrate of protein kinase C. .1 Biol Chem 1983: 258: 11423-11426. 105. Jaken S, Leach K. Klauck T. Association of type 3 protein kinase C with focal contacts in rat embryo llbioblasts. .1 Cell Biol 1989: 109: 697 704. 106. Tsukitani S, Oishi K, Akiyama T, Yamanishi Y, Yaniamoto T. Tsukitani S. Speeific proto-oncogenic tyrosine kinases of src family are enriched in cell-to-ccll adherens junctions where the level of tyrosine phosphorylation is elevated. .1 Cell Biol 1991: 113: 867-879. 107. O'Keefe E J. Briggaman R A, Herman B. Calcium-induced assembly of adherens junctions in keratinocytes. .1 Cell Biol 1987:' 105: 807-817. 108. Rosen A, Keenan K F, Thelen M, Narin A C. Aderem A. Activation of protein kinase C results in the displaeement of ils niyriostoylaled. alanine-rich substrate from punctates in macrophage filopodia. .1 Fxp Med 1990: 172: 1211-1215. 109. Thelen M. Rosen A. Narin A C, Aderem A. Regulation by phosphorylation of reversible association of a myristoylaled protein kinase C substi'ate with llie plasma membrane. Nature 1991: 351: 320 322. 110. Hartwig J H, Thelen M. Rosen A, .lanmey P A, Nairn A C. Aderem A. MARCKS is an actin filament crosslinking protein regulated by protein kinase C and calcium-calmodtiljn. Nature 1992! 356: 618-622.
111. Sheu H-M. Kitajima Y. Yaoita H. Involvement of protein kinase C in translocation of desmoplakin from cytosol to plasma membrane during desmosome formation in human squamous cell carcinoma cells grown in low to normal calcium concentration. Exp Cell Res 1989: 185: 176-190. 112. Inohara S. Tatsumi Y. Cho H. Tanaka Y, Sagami S. Actin filament and desmosome formation in cultured human keratinocytes. Arch Dermatol Res 1990: 282: 210-212. 113. Inohara S. Tatsumi Y. Tanaka Y. Sagami S. Immunohistochemical localization of desmosomal and cytoskeletal proteins in the epidermis of healthy individuals and patients with Hailey-Hailey's di.sea.se. Aeta Derm Venereol (Stockh) 1990: 70: 239-241. 114. Eisinger M, Mark O. Selective proliferation of normal human melanocytes in vitro in the presence of phorbol ester and cholera toxin. Proc Natl Acad Sci USA 1982: 79: 2018-2022. 115. Halaban R, Langdon R. Birchall N. et al. Basic fibroblast growth factor from human keratinoeytes is a natural mitogen for melanocytes. .1 Cell Biol 1988: 107: 1611-1619. 116. Yaar M, Gilchrest BA. Human melanocyte growth and differentiation: a decade of new data. .1 Invest Dermatol 1991: 97: 611-617. 117. Gordon P R, Gilchrest B A. Human melanogenesis is stimulated by diaeylglyeerol. .1 Invest Dermatol 1989: 93: 700-702. 118. Friedmann P S, Wren F E, Matthews .1 N S. Ultraviolet stimulated melanogenesis by human melanocytes is augmented by diacylglycerol but not TPA. .1 Cell Physiol 1990: 142: 334-.341. 119. Brooks G, Wilson R E. Dooley T P. Gross M W. Hart 1 R. Protein kinase C downregulation, and not transient activation, correlates with melanocyte growth. Cancer Res 1991: 51: 3281-3288. 120. Iwamoto T. Takahashi M, Ito M, et al. Aberrant melanogenesis and melanocytic tumor development in transgenic mice that carry a metallothionein/rrv fusion gene. EMBO.1 1991: 10: 3167-3175. ' - ' • Halliday G M. Odling K A, Ruby .1 C, Muller H K. Suppressor cell activation and enhanced skin allograft survival after tumor promoter but not initiator induced depletion of cutaneous Langerhans cells. .1 Invest Dermatol 1988: 90: 293-297. Czernielewski .1 M. Demarchez M. Further evidence for 122. the self-reproducing capacity of Langerhans cells in human skin. .1 Invest Dermatol 1987: 88: 17-20. Koyama Y. Hachiya T. Hagiwara M. et al. Expression of 123. protein kinase C isozynie in epidermal Langerhans cells of the mouse. .1 Invest' Dermatol 1990: 94: 677-680. Koyama Y. Eukaya Y, Ueda H, et al. Expression of pro124. tein kinase C isozyme in human Langerhans' cells. Acta Derm Venereol (St'ockh) 1990: 70: 502-505. Moore G P M. Panaretto B A. Robertson D .1. Effects of 125. epidermal growth factor on hair growth in the mouse. Endocrinology 1981: 88: 293-299. Philport M P. Green M R, Kealey T. Human hair growth 126. /;, vitro. J Cell Sci 1990: 97: 46.3^71. Green M R, Couehman .1 R. Distribution and number of 127. epidermal growth factor receptors in rat tissues during embryonic development, hair formation, and the adult hair growth cycle. .1 Invest Dermatol 1984: 83: 118-123. Nanney L B. Magid M, Stoscheck M. King L E. Compari128. son of epidermal growth factor binding and receptor distribution in normal human epidermis and epidermal appandages. .1 Invest Dermatol 1984: 83: 385-393. 129. Ogawa H, Hallori M. Regulation mechanistiis of hair growth. In: Seiji M. Bernstein I A. eds. Abnormal Epidermal Differentiation. Tokyo: University of Tokyo Press, 198.3: 159-170.
219
Inohara 130. Kono T, Fukuda M, Ishii M, et al. Detection of ornithine decarboxylase gene expression in 12-O-tetradecanoylphorbol-13-acetate-treated mouse skin using in situ hybridization. Acta Derm Venereol (Stockh) 1991: 71: 104-107. 131. Priestley G C, Adams L W. Hyperactivity of fibroblasts cultured from psoriatic skin, I. Faster proliferation and effect of serum withdrawal. Br .1 Dermatol 1983: 109: 149-156. 132. Priestley G C, Adams L W. Mitogenic effeets of sera from normal and psoriatic subjects on human fibroblasts. Arch Dermatol Res 1985: 277:' 13-15. 133. Brion D E, Raynaud E, Plet A, Laurent P. Leduc B, Anderson W. Deficiency of cyclic AMP-dependent protein kinase in human psoriasis. Proc Natl Acad Sci USA 1986: 83: 5722-5726. 134. Nagao S, Seishima M, Mori S, Nozawa Y. Increased protein kinase C activity in fibroblast membranes from psoriatie patients. J Invest Dermatol 1988: 90: 406-408. 135. Raynaud E, Evain-Brion D. Protein kinase C activity in normal and psoriatic cells: cultures of fibroblasts and lymphocytes. Br .1 Dermatol 1991: 124: 542-546. 136. Davison P M, Bensch K G, Kara.sek M A. Isolation and growth of endothelial cells from the microvessels of the newborn human foreskin in cell culture. J Invest Dermatol 1980: 75: 316-321. 137. Karasek M A. Microvascular endothelial cell culture. J Invest Dermatol 1989: 93: 3.3-38. 138. Karasek M A. Mechanisms of angiogenesis in normal and diseased skin. Int J Dermatol 1991: 30: 831-836. 139. Davison P M, Karasek M A. Human dermal microvascular endothelial cells in vitro: effects of cyclic AMP on cellular morphology and proliferation rate. .1 Cell Physiol 1981: 106: 253-258. 140. Tuder R M, Karasek M A, Bensch K G. Cyclic adenosine monophosphate levels and the function of skin microvascular endothelial cells. J Cell Physiol 1990: 142: 272-283. 141. Hall A. The cellular functios of .small GTP-binding proteins. Science 1990: 249: 635-640.
220
142. Kikuchi A, Yamashita T, Kawata M, et al. Purification and characterization of a novel GTP-binding protein with a molecular weight of 24,000 from bovine brain membranes. J Biol Chem 1988: 263: 2897-2904. 143. Matsui Y, Kikuchi A. Kondo J, Hishida T, Teranishi Y, Takai Y. Nucleotide and deduced amino acid sequences of a GTP-binding protein family with molecular weight of 25,000 from bovine brain. J Biol Chem 1988- ''6311071-11074. 144. Mizoguchi A, Kim S, Ueda T, Takai Y. Tissue distribution of ,s7»g p25A, a ra.v p21-like GTP-binding protein, studied by use of a specific monoclonal antibody. Biochem Biophys Res Commun 1989: 162: 1438-1445. 145. Inohara S, Tanaka Y, Kitano Y, et al. Immunohistological localization of smg p25A. a ras p21-like guanosine 5'triphosphate (GTP)-binding protein in human skin. Arch Dermatol Res 1992: 284: 109-110. 146. Morita M, Yamagata M, Inohara S, Sagami S. Flow cytometric analysis of protein kinase C in lymph node cells during the induction phase of contact hypersensitivity reaction. J Dermatol (Tokyo) 1989: 16: 352-354. 147. Amon U, Dietz K R. Protein kinase C: a target for antiinfiammatory therapy? Arch Dermatol Res 1992' 7848-10. 148. Hanks S K, Quinn A M, Hunter T. The protein kinase family: eonserved features and deduced phylogeny of tbe catalytic domains. Science 1988: 241: 42-52. 149. Osada S, Mizuno K, Saido T C, et al. A phorbol ester receptor/protein kinase C, nPKCii, a new member of the protein kinase C family predominantly expressed in lung and skin. J Biol Chem 1990: 265: 22434-22440. 150. Gherzi R, Sparatore B, Patrone M, Sciutto A, Briata P. Protein kinase C mRNA levels and activity in reconstituted normal human epidermis: relationships to cell differentiation. Biochem Biophys Res Commun 199"'- 184283-291.
