Effector enzymes coupled to GTP binding proteins

Ras-associating (RA) domains, is intermediate between receptor activation and the MAP-kinase pathway leading to mitogenesis.51 The PLC isoform is a multifunctional entity that senses and mediates cross-talk between the pathways set in train by both the heterotrimeric and the Ras-like GTPases.58

PLC is activated through interaction with a protein tyrosine kinase

The isoforms of PLC possess an additional region, absent from the and forms, inserted between the X and Y sequences of the catalytic domain (see Figure 5.11). This region contains one SH3 domain and two SH2 domains.

PLC is present in cells that have receptors with intrinsic tyrosine kinase activity (Chapter 12) and which bind growth factors (e.g. EGF, PDGF, FGF, and IGF) and also in cells with receptors of the immunoglobulin superfamily,

which recruit non-receptor protein tyrosine kinases (T and B lymphocytes and mast cells; Chapter 17). The SH2 domains of PLC enable it to bind to motifs on the intracellular chains of receptors that have become phosphorylated on tyrosine residues following the binding of a stimulatory ligand (Chapter 12). This brings PLC into a signalling complex, where it becomes phosphorylated itself by the tyrosine kinase activity of the receptor (or accessory, non-receptor tyrosine kinase). This causes its activation.

References

 1. Rall TW, Sutherland EW, Berthet J. The relationship of epinephrine and glucagon to liver phosphorylase: effect of epinephrine and glucagon on the reactivation of phosphorylase in liver homogenates. J Biol Chem. 1957;224:463–475.

 2. Nakamura T, Tomomura A, Kato S, Noda C, Ichihara A. Reciprocal expressions of 1- and -adrenergic receptors, but constant expression of glucagon receptor by rat hepatocytes during development and primary culture. J Biochem Tokyo. 1984;96:127–136.

 3. Botsford JL, Harman JG. Cyclic AMP in prokaryotes. Microbiol Rev. 1992;56:100–122.

 4. Leichtling BH, Rickenberg HV, Seely RJ, Fahrney DE, Pace NR. The occurrence of cyclic AMP in archaebacteria. Biochem Biophys Res Commun. 1986;136:1078–1082.

 5. Bolwell GP. Cyclic AMP, the reluctant messenger in plants. Trends Biochem Sci. 1995;20:492–495.

 6. Li WW, Luan S, Schreiber SL, Assmann SM. CyclicAMP stimulates

K channel activity in mesophyll cells of Vicia faba K. Plant Physiol. 1994;105:957–961.

 7. Wu WH, Assmann SM. A membrane delimited pathway of G-protein regulation of the guard cell inward K channel. Proc Natl Acad Sci U S A. 1994;91:6310–6314.

153

Signal Transduction

 8. Sutherland EW, Rall TW, Menon T. Adenyl cyclase: distribution, preparation and properties. J Biol Chem. 1962;237:1220–1227.

 9. Sutherland EW. Studies on the mechanism of hormone action. Science. 1972;177:401–408.

10.Sunahara RK, Dessauer CW, Gilman AG. Complexity and diversity of mammalian adenylyl cyclases. Annu Rev Pharmacol Toxicol. 1996;36:461–480.

11.Tang W-J, Hurley JH. Catalytic mechanism and regulation of mammalian adenylyl cyclase. Mol Pharmacol. 1998;54:231–240.

12.Dessauer CW, Gilman AG. Purification and characterization of a soluble form of mammalian adenylyl cyclase. J Biol Chem. 1996;271:16967–16974.

13.Yan SZ, Hahn D, Huang ZH, Tang WJ. Two cytoplasmic domains of mammalian adenylyl cyclase form a Gs - and forskolin-activated enzyme in vitro. J Biol Chem. 1996;271:10941–10945.

14.Whisnant RE, Gilman AG, Dessauer CW. Interaction of the two cytosolic domains of mammalian adenylyl cyclase. Proc Natl Acad Sci U S A. 1996;93:6621–6625.

15.van Veen HW, Margolles A, Muller M, Higgins CF, Konings WN. The homodimeric ATP-binding cassette transporter LmrA mediates multidrug transport by an alternating two-site (two-cylinder engine) mechanism. EMBO J. 2000;19:2503–2514.

16.Post SR, Hilal-Dandan R, Urasawa K, Brunton LL, Insel PA. Quantification of signalling components and amplification in the -adrenergic-receptor- adenylate cyclase pathway in isolated rat ventricular myocytes. Biochem J. 1995;311:75–80.

17.MacEwan DJ, Kim GD, Milligan G. Agonist regulation of adenylate cyclase activity in neuroblastoma glioma hybrid NG109-15 cells transfected to co-express adenylate cyclase type II and the 2-adrenoceptor. Evidence that adenylate cyclase is the limiting component for receptor-mediated stimulation of adenylate cyclase activity. Biochem J. 1996;318:1033–1039.

18.Hanoune J, Defer N. Regulation and role of adenylyl cyclase isoforms.

Annu Rev Pharmacol Toxicol. 2001;41:145–174.

19.Krumins AM, Gilman AG. Targeted knockdown of G protein subunits selectively prevents receptor-mediated modulation of effectors and reveals complex changes in non-targeted signaling proteins. J Biol Chem. 2006;281:10250–10262.

20.Sattin A, Rall TW, Zanella J. Regulation of cyclic adenosine 3 ,5 - monophosphate levels in guinea-pig cerebral cortex by interaction of-adrenergic and adenosine receptor activity. J Pharmacol Exp Ther. 1975;192:22–32.

21.Sternweis PC. The active role of in signal transduction. Curr Opinion Cell Biol. 1994;6:198–203.

22.Willoughby D, Cooper DM. Organization and Ca2 regulation of adenylyl cyclases in cAMP microdomains. Physiol Rev. 2007;87:965–1010.

154

Effector enzymes coupled to GTP binding proteins

23.Rodbell M. Metabolism of isolated fat cells. V. Preparation of ‘ghosts’ and their properties; adenyl cyclase and other enzymes. J Biol Chem. 1967;242:5744–5750.

24.Birnbaumer L, Pohl SL, Rodbell M. Adenyl cyclase in fat cells. 1. Properties and the effects of adrenocorticotropin and fluoride. J Biol Chem. 1969;244:3468–3476.

25.Sternweis PC, Gilman AG. Aluminum: a requirement for activation of the regulatory component of adenylate cyclase by fluoride. Proc Natl Acad Sci U S A. 1982;79:4888–4891.

26.Mittal R, Ahmadian MR, Goody RS, Wittinghofer A. Formation of a transition-state analog of the Ras GTPase reaction by Ras-GDP, tetrafluoroaluminate, and GTPase-activating proteins. Science.

1996;273:115–117.

27.Harwood JP, Low H, Rodbell M. Stimulatory and inhibitory effects of guanyl nucleotides on fat cell adenylate cyclase. J Biol Chem. 1973;248:6239–6245.

28.Harwood JP, Rodbell M. Inhibition by fluoride ion of hormonal activation of fat cell adenylate cyclase. J Biol Chem. 1973;248: 4901–4904.

29.Daemen FJ. Vertebrate rod outer segment membranes. Biochim Biophys Acta. 1973;300:255–288.

30.Kuhn H, Bennett N, Michel-Villaz M, Chabre M. Interactions between photoexcited rhoddopsin and GTP-binding protein: kinetic and stoichiometric analyses from light scattering changes. Proc Natl Acad Sci USA. 1981;78:6877.

31.Laurenza A, Sutkowski EM, Seamon KB. Forskolin: a specific stimulator of adenylyl cyclase or a diterpene with multiple sites of action? Trends Pharmacol Sci 1989;10:442–447.

32.Peterson JW, Ochoa LG. Role of prostaglandins and cAMP in the secretory effects of cholera toxin. Science. 1989;245:857–859.

33.Pittman M. The concept of pertussis as a toxin-mediated disease. Pediatr Infect Dis. 1984;3:467–486.

34.Gill DM, Meren R. ADP-ribosylation of membrane proteins catalyzed by cholera toxin: basis of the activation of adenylate cyclase. Proc Natl Acad Sci U S A. 1978;75:3050–3054.

35.Cassel D, Pfeiffer T. Mechanism of cholera toxin action: covalent modification of the guanyl nucleotide-binding protein of the adenylate cyclase system. Proc Natl Acad Sci U S A. 1978;75:2669–2673.

36.Seo HS, Kim HY, Jeong JY, Lee SY, Cho MJ, Bahk JD. Molecular cloning and characterization of RGA1 encoding a G protein subunit from rice (Oryza sativa L. IR-36). Plant Mol Biol. 1995;27:1119–1131.

37.Wu WH, Assmann SM. A membrane-delimited pathway of G-protein regulation of the guard-cell inward K channel. Proc Natl Acad Sci U S A. 1994;91:6310–6314.

155

Signal Transduction

38.Katada T, Ui M. Direct modification of the membrane adenylate cyclase system by islet activating protein due to ADP-ribosylation of a membrane protein. Proc Natl Acad Sci U S A. 1982;79:3129–3133.

39.Pfeuffer T. GTP-binding proteins in membranes and the control of adenylate cyclase activity. J Biol Chem. 1977;252:7224–7234.

40.Pfeuffer T, Helmreich EJ. Activation of pigeon erythrocyte membrane adenylate cyclase by guanylnucleotide analogues and separation of a nucleotide binding protein. J Biol Chem. 1975;250:867–876.

41.Landis CA, Masters SB, Spada A, Pace AM, Bourne HR, Vallar L. GTPase inhibiting mutations activate the chain of Gs and stimulate adenylate cyclase in human pituitary tumours. Nature. 1989;340:690–696.

42.Lyons J, Landis CA, Harsh G, et al. Two G protein oncogenes in human endocrine tumors. Science. 1990;245:655–659.

43.Lupi R, Corda D, Di Girolamo M. Endogenous ADP-ribosylation of the G-Protein subunit prevents the inhibition of type 1 adenylyl cyclase. J Biol Chem. 2000;275:9418–9424.

44.Lupi R, Dani N, Dietrich A, et al. Endogenous mono-ADP-ribosylation of the free G prevents stimulation of phosphoinositide 3-kinase- and phospholipase C- 2 and is activated by G-protein-coupled receptors.

Biochem J. 2002;367:825–832.

45.Di GM, Dani N, Stilla A, Corda D. Physiological relevance of the endogenous mono(ADP-ribosyl)ation of cellular proteins. FEBS J. 2005;272:4565–4575.

46.Hokin MR, Hokin LE. Enzyme secretion and the incorporation of 32P into phospholipides of pancreas slices. J Biol Chem. 1953;203:967–977.

47.Michell RH. Inositol phospholipids in cell surface receptor function.

Biochim Biophys Acta. 1975;415:81–147.

48.Creba JA, Downes CP, Hawkins PT, Brewster G, Michell RH, Kirk CJ. Rapid breakdown of phosphatidylinositol 4-phosphate and

phosphatidylinositol 4,5-bisphosphate in rat hepatocytes stimulated by vasopressin and other Ca2 -mobilizing hormones. Biochem J. 1983;212:733–747.

49.Streb H, Irvine RF, Berridge MJ, Schultz I. Release of Ca2 from a nonmitochondrial intracellular store in pancreatic acinar cells by inositol- 1,4,5-trisphosphate. Nature. 1983;306:67–69.

50.Song C, Hu C-D, Masago M, et al. Regulation of a novel human phospholipase C, PLC , through membrane targeting by ras. J Biol Chem. 2001;276:2752–2757.

51.Lopez I, Mak EC, Ding J, Hamm HE, Lomasney JW. A novel bifunctional phospholipase C that is regulated by G 12 and stimulates the Ras/ mitogen-activated protein kinase pathway. J Biol Chem. 2001;276: 2758–2765.

52.Irvine R. Phospholipid signaling. Taking stock of PI-PLC. Nature. 1996;380:581–583.

156

Effector enzymes coupled to GTP binding proteins

53.Essen L-O, Perisic O, Cheung R, Katan M, Williams RL. Crystal structure of a mammalian phosphoinositide-specific phospholipase C . Nature. 1996;380:595–602.

54.Katan M, Williams RL. Phosphoinositide-specific phospholipase

C: structural basis for catalysis and regulatory interactions. Semin Cell Dev Biol. 1997;8:287–296.

55.Kuang Y, Wu Y, Smrcka A, Jiang H, Wu D. Identification of a phospholipase C 2 region that interacts with G . Proc Natl Acad Sci U S A. 1996;93: 2964–2968.

56.Lee SB, Shin SH, Hepler JR, Gilman AG, Rhee SG. Activation of

phospholipase C 2 mutants by G protein q and subunits. J Biol Chem. 1993;268:25952–25957.

57.Rhee SG. Regulation of phosphoinositide-specific phospholipase C. Annu Rev Physiol. 2001;70:281–312.

58.Wing MR, Bourdon DM, Harden TK. PLC- : a shared effector protein in Ras-, Rho-, and G -mediated signaling. Mol Interv. 2003;3:273–280.

157