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. 1996 Jul 1;15(13):3361–3368.

Dual role of cAMP and involvement of both G-proteins and ras in regulation of ERK2 in Dictyostelium discoideum.

M L Knetsch 1, S J Epskamp 1, P W Schenk 1, Y Wang 1, J E Segall 1, B E Snaar-Jagalska 1
PMCID: PMC451899  PMID: 8670837

Abstract

Dictyostelium discoideum expresses two Extracellular signal Regulated Kinases, ERK1 and ERK2, which are involved in growth, multicellular development and regulation of adenylyl cyclase. Binding of extracellular cAMP to cAMP receptor 1, a G-protein coupled cell surface receptor, transiently stimulates phosphorylation, activation and nuclear translocation of ERK2. Activation of ERK2 by cAMP is dependent on heterotrimeric G-proteins, since activation of ERK2 is absent in cells lacking the Galpha4 subunit. The small G-protein rasD also activates ERK2. In cells overexpressing a mutated, constitutively active rasD, ERK2 activity is elevated prior to cAMP stimulation. Intracellular cAMP and cAMP-dependent protein kinase (PKA) are essential for adaptation of the ERK2 response. This report shows that multiple signalling pathways are involved in regulation of ERK2 activity in D.discoideum.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Avruch J., Zhang X. F., Kyriakis J. M. Raf meets Ras: completing the framework of a signal transduction pathway. Trends Biochem Sci. 1994 Jul;19(7):279–283. doi: 10.1016/0968-0004(94)90005-1. [DOI] [PubMed] [Google Scholar]
  2. Blumer K. J., Johnson G. L. Diversity in function and regulation of MAP kinase pathways. Trends Biochem Sci. 1994 Jun;19(6):236–240. doi: 10.1016/0968-0004(94)90147-3. [DOI] [PubMed] [Google Scholar]
  3. Boulton T. G., Nye S. H., Robbins D. J., Ip N. Y., Radziejewska E., Morgenbesser S. D., DePinho R. A., Panayotatos N., Cobb M. H., Yancopoulos G. D. ERKs: a family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF. Cell. 1991 May 17;65(4):663–675. doi: 10.1016/0092-8674(91)90098-j. [DOI] [PubMed] [Google Scholar]
  4. Brenner M., Thoms S. D. Caffeine blocks activation of cyclic AMP synthesis in Dictyostelium discoideum. Dev Biol. 1984 Jan;101(1):136–146. doi: 10.1016/0012-1606(84)90124-6. [DOI] [PubMed] [Google Scholar]
  5. Burgering B. M., Bos J. L. Regulation of Ras-mediated signalling: more than one way to skin a cat. Trends Biochem Sci. 1995 Jan;20(1):18–22. doi: 10.1016/s0968-0004(00)88944-6. [DOI] [PubMed] [Google Scholar]
  6. Burgering B. M., Medema R. H., Maassen J. A., van de Wetering M. L., van der Eb A. J., McCormick F., Bos J. L. Insulin stimulation of gene expression mediated by p21ras activation. EMBO J. 1991 May;10(5):1103–1109. doi: 10.1002/j.1460-2075.1991.tb08050.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Burgering B. M., Pronk G. J., van Weeren P. C., Chardin P., Bos J. L. cAMP antagonizes p21ras-directed activation of extracellular signal-regulated kinase 2 and phosphorylation of mSos nucleotide exchange factor. EMBO J. 1993 Nov;12(11):4211–4220. doi: 10.1002/j.1460-2075.1993.tb06105.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chen R. H., Sarnecki C., Blenis J. Nuclear localization and regulation of erk- and rsk-encoded protein kinases. Mol Cell Biol. 1992 Mar;12(3):915–927. doi: 10.1128/mcb.12.3.915. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Chuang E., Barnard D., Hettich L., Zhang X. F., Avruch J., Marshall M. S. Critical binding and regulatory interactions between Ras and Raf occur through a small, stable N-terminal domain of Raf and specific Ras effector residues. Mol Cell Biol. 1994 Aug;14(8):5318–5325. doi: 10.1128/mcb.14.8.5318. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Clarke M., Yang J., Kayman S. C. Analysis of the prestarvation response in growing cells of Dictyostelium discoideum. Dev Genet. 1988;9(4-5):315–326. doi: 10.1002/dvg.1020090413. [DOI] [PubMed] [Google Scholar]
  11. Cook S. J., McCormick F. Inhibition by cAMP of Ras-dependent activation of Raf. Science. 1993 Nov 12;262(5136):1069–1072. doi: 10.1126/science.7694367. [DOI] [PubMed] [Google Scholar]
  12. Crespo P., Xu N., Simonds W. F., Gutkind J. S. Ras-dependent activation of MAP kinase pathway mediated by G-protein beta gamma subunits. Nature. 1994 Jun 2;369(6479):418–420. doi: 10.1038/369418a0. [DOI] [PubMed] [Google Scholar]
  13. Crews C. M., Alessandrini A., Erikson R. L. The primary structure of MEK, a protein kinase that phosphorylates the ERK gene product. Science. 1992 Oct 16;258(5081):478–480. doi: 10.1126/science.1411546. [DOI] [PubMed] [Google Scholar]
  14. Daniel J., Bush J., Cardelli J., Spiegelman G. B., Weeks G. Isolation of two novel ras genes in Dictyostelium discoideum; evidence for a complex, developmentally regulated ras gene subfamily. Oncogene. 1994 Feb;9(2):501–508. [PubMed] [Google Scholar]
  15. Devreotes P. N. G protein-linked signaling pathways control the developmental program of Dictyostelium. Neuron. 1994 Feb;12(2):235–241. doi: 10.1016/0896-6273(94)90267-4. [DOI] [PubMed] [Google Scholar]
  16. Devreotes P. Dictyostelium discoideum: a model system for cell-cell interactions in development. Science. 1989 Sep 8;245(4922):1054–1058. doi: 10.1126/science.2672337. [DOI] [PubMed] [Google Scholar]
  17. Faure M., Voyno-Yasenetskaya T. A., Bourne H. R. cAMP and beta gamma subunits of heterotrimeric G proteins stimulate the mitogen-activated protein kinase pathway in COS-7 cells. J Biol Chem. 1994 Mar 18;269(11):7851–7854. [PubMed] [Google Scholar]
  18. Firtel R. A., van Haastert P. J., Kimmel A. R., Devreotes P. N. G protein linked signal transduction pathways in development: dictyostelium as an experimental system. Cell. 1989 Jul 28;58(2):235–239. doi: 10.1016/0092-8674(89)90837-4. [DOI] [PubMed] [Google Scholar]
  19. Frödin M., Peraldi P., Van Obberghen E. Cyclic AMP activates the mitogen-activated protein kinase cascade in PC12 cells. J Biol Chem. 1994 Feb 25;269(8):6207–6214. [PubMed] [Google Scholar]
  20. Gaskins C., Clark A. M., Aubry L., Segall J. E., Firtel R. A. The Dictyostelium MAP kinase ERK2 regulates multiple, independent developmental pathways. Genes Dev. 1996 Jan 1;10(1):118–128. doi: 10.1101/gad.10.1.118. [DOI] [PubMed] [Google Scholar]
  21. Gaskins C., Maeda M., Firtel R. A. Identification and functional analysis of a developmentally regulated extracellular signal-regulated kinase gene in Dictyostelium discoideum. Mol Cell Biol. 1994 Oct;14(10):6996–7012. doi: 10.1128/mcb.14.10.6996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Gunzburg J., Veron M. A cAMP-dependent protein kinase is present in differentiating Dictyostelium discoideum cells. EMBO J. 1982;1(9):1063–1068. doi: 10.1002/j.1460-2075.1982.tb01297.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Hadwiger J. A., Firtel R. A. Analysis of G alpha 4, a G-protein subunit required for multicellular development in Dictyostelium. Genes Dev. 1992 Jan;6(1):38–49. doi: 10.1101/gad.6.1.38. [DOI] [PubMed] [Google Scholar]
  24. Hadwiger J. A., Lee S., Firtel R. A. The G alpha subunit G alpha 4 couples to pterin receptors and identifies a signaling pathway that is essential for multicellular development in Dictyostelium. Proc Natl Acad Sci U S A. 1994 Oct 25;91(22):10566–10570. doi: 10.1073/pnas.91.22.10566. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Harwood A. J., Hopper N. A., Simon M. N., Bouzid S., Veron M., Williams J. G. Multiple roles for cAMP-dependent protein kinase during Dictyostelium development. Dev Biol. 1992 Jan;149(1):90–99. doi: 10.1016/0012-1606(92)90266-j. [DOI] [PubMed] [Google Scholar]
  26. Herskowitz I. MAP kinase pathways in yeast: for mating and more. Cell. 1995 Jan 27;80(2):187–197. doi: 10.1016/0092-8674(95)90402-6. [DOI] [PubMed] [Google Scholar]
  27. Hordijk P. L., Verlaan I., Jalink K., van Corven E. J., Moolenaar W. H. cAMP abrogates the p21ras-mitogen-activated protein kinase pathway in fibroblasts. J Biol Chem. 1994 Feb 4;269(5):3534–3538. [PubMed] [Google Scholar]
  28. Howe L. R., Leevers S. J., Gómez N., Nakielny S., Cohen P., Marshall C. J. Activation of the MAP kinase pathway by the protein kinase raf. Cell. 1992 Oct 16;71(2):335–342. doi: 10.1016/0092-8674(92)90361-f. [DOI] [PubMed] [Google Scholar]
  29. Jain R., Yuen I. S., Taphouse C. R., Gomer R. H. A density-sensing factor controls development in Dictyostelium. Genes Dev. 1992 Mar;6(3):390–400. doi: 10.1101/gad.6.3.390. [DOI] [PubMed] [Google Scholar]
  30. Janssens P. M., Van Haastert P. J. Molecular basis of transmembrane signal transduction in Dictyostelium discoideum. Microbiol Rev. 1987 Dec;51(4):396–418. doi: 10.1128/mr.51.4.396-418.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Klein P. S., Sun T. J., Saxe C. L., 3rd, Kimmel A. R., Johnson R. L., Devreotes P. N. A chemoattractant receptor controls development in Dictyostelium discoideum. Science. 1988 Sep 16;241(4872):1467–1472. doi: 10.1126/science.3047871. [DOI] [PubMed] [Google Scholar]
  32. Koch W. J., Hawes B. E., Allen L. F., Lefkowitz R. J. Direct evidence that Gi-coupled receptor stimulation of mitogen-activated protein kinase is mediated by G beta gamma activation of p21ras. Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12706–12710. doi: 10.1073/pnas.91.26.12706. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Lange-Carter C. A., Pleiman C. M., Gardner A. M., Blumer K. J., Johnson G. L. A divergence in the MAP kinase regulatory network defined by MEK kinase and Raf. Science. 1993 Apr 16;260(5106):315–319. doi: 10.1126/science.8385802. [DOI] [PubMed] [Google Scholar]
  34. Leevers S. J., Marshall C. J. Activation of extracellular signal-regulated kinase, ERK2, by p21ras oncoprotein. EMBO J. 1992 Feb;11(2):569–574. doi: 10.1002/j.1460-2075.1992.tb05088.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Lilly P., Wu L., Welker D. L., Devreotes P. N. A G-protein beta-subunit is essential for Dictyostelium development. Genes Dev. 1993 Jun;7(6):986–995. doi: 10.1101/gad.7.6.986. [DOI] [PubMed] [Google Scholar]
  36. Liu G., Newell P. C. Regulation of myosin regulatory light chain phosphorylation via cyclic GMP during chemotaxis of Dictyostelium. J Cell Sci. 1994 Jul;107(Pt 7):1737–1743. doi: 10.1242/jcs.107.7.1737. [DOI] [PubMed] [Google Scholar]
  37. Macdonald S. G., Crews C. M., Wu L., Driller J., Clark R., Erikson R. L., McCormick F. Reconstitution of the Raf-1-MEK-ERK signal transduction pathway in vitro. Mol Cell Biol. 1993 Nov;13(11):6615–6620. doi: 10.1128/mcb.13.11.6615. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Nestle M., Sussman M. The effect of cyclic AMP on morphogernesis and enzyme accumulation in Dictyostelium discoideum. Dev Biol. 1972 Aug;28(4):545–554. doi: 10.1016/0012-1606(72)90002-4. [DOI] [PubMed] [Google Scholar]
  39. Pitt G. S., Milona N., Borleis J., Lin K. C., Reed R. R., Devreotes P. N. Structurally distinct and stage-specific adenylyl cyclase genes play different roles in Dictyostelium development. Cell. 1992 Apr 17;69(2):305–315. doi: 10.1016/0092-8674(92)90411-5. [DOI] [PubMed] [Google Scholar]
  40. Ray L. B., Sturgill T. W. Insulin-stimulated microtubule-associated protein kinase is phosphorylated on tyrosine and threonine in vivo. Proc Natl Acad Sci U S A. 1988 Jun;85(11):3753–3757. doi: 10.1073/pnas.85.11.3753. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Reymond C. D., Gomer R. H., Mehdy M. C., Firtel R. A. Developmental regulation of a Dictyostelium gene encoding a protein homologous to mammalian ras protein. Cell. 1984 Nov;39(1):141–148. doi: 10.1016/0092-8674(84)90199-5. [DOI] [PubMed] [Google Scholar]
  42. Reymond C. D., Gomer R. H., Nellen W., Theibert A., Devreotes P., Firtel R. A. Phenotypic changes induced by a mutated ras gene during the development of Dictyostelium transformants. 1986 Sep 25-Oct 1Nature. 323(6086):340–343. doi: 10.1038/323340a0. [DOI] [PubMed] [Google Scholar]
  43. Robbins S. M., Williams J. G., Jermyn K. A., Spiegelman G. B., Weeks G. Growing and developing Dictyostelium cells express different ras genes. Proc Natl Acad Sci U S A. 1989 Feb;86(3):938–942. doi: 10.1073/pnas.86.3.938. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Satoh T., Endo M., Nakafuku M., Nakamura S., Kaziro Y. Platelet-derived growth factor stimulates formation of active p21ras.GTP complex in Swiss mouse 3T3 cells. Proc Natl Acad Sci U S A. 1990 Aug;87(15):5993–5997. doi: 10.1073/pnas.87.15.5993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Segall J. E., Kuspa A., Shaulsky G., Ecke M., Maeda M., Gaskins C., Firtel R. A., Loomis W. F. A MAP kinase necessary for receptor-mediated activation of adenylyl cyclase in Dictyostelium. J Cell Biol. 1995 Feb;128(3):405–413. doi: 10.1083/jcb.128.3.405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Seth A., Gonzalez F. A., Gupta S., Raden D. L., Davis R. J. Signal transduction within the nucleus by mitogen-activated protein kinase. J Biol Chem. 1992 Dec 5;267(34):24796–24804. [PubMed] [Google Scholar]
  47. Simon M. N., Pelegrini O., Veron M., Kay R. R. Mutation of protein kinase A causes heterochronic development of Dictyostelium. Nature. 1992 Mar 12;356(6365):171–172. doi: 10.1038/356171a0. [DOI] [PubMed] [Google Scholar]
  48. Snaar-Jagalska B. E., Devreotes P. N., Van Haastert P. J. Ligand-induced modification of a surface cAMP receptor of Dictyostelium discoideum does not require its occupancy. J Biol Chem. 1988 Jan 15;263(2):897–901. [PubMed] [Google Scholar]
  49. Snaar-Jagalska B. E., Kesbeke F., Van Haastert P. J. G-proteins in the signal-transduction pathways of Dictyostelium discoideum. Dev Genet. 1988;9(4-5):215–226. doi: 10.1002/dvg.1020090404. [DOI] [PubMed] [Google Scholar]
  50. Soede R. D., Insall R. H., Devreotes P. N., Schaap P. Extracellular cAMP can restore development in Dictyostelium cells lacking one, but not two subtypes of early cAMP receptors (cARs). Evidence for involvement of cAR1 in aggregative gene expression. Development. 1994 Jul;120(7):1997–2002. doi: 10.1242/dev.120.7.1997. [DOI] [PubMed] [Google Scholar]
  51. Van Haastert P. J., Janssens P. M., Erneux C. Sensory transduction in eukaryotes. A comparison between Dictyostelium and vertebrate cells. Eur J Biochem. 1991 Jan 30;195(2):289–303. doi: 10.1111/j.1432-1033.1991.tb15706.x. [DOI] [PubMed] [Google Scholar]
  52. Van Haastert P. J., Kesbeke F., Reymond C. D., Firtel R. A., Luderus E., Van Driel R. Aberrant transmembrane signal transduction in Dictyostelium cells expressing a mutated ras gene. Proc Natl Acad Sci U S A. 1987 Jul;84(14):4905–4909. doi: 10.1073/pnas.84.14.4905. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Van Ments-Cohen M., Van Haastert P. J. The cyclic nucleotide specificity of eight cAMP-binding proteins in Dictyostelium discoideum is correlated into three groups. J Biol Chem. 1989 May 25;264(15):8717–8722. [PubMed] [Google Scholar]
  54. Watts D. J., Ashworth J. M. Growth of myxameobae of the cellular slime mould Dictyostelium discoideum in axenic culture. Biochem J. 1970 Sep;119(2):171–174. doi: 10.1042/bj1190171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Williams J. G. The role of diffusible molecules in regulating the cellular differentiation of Dictyostelium discoideum. Development. 1988 May;103(1):1–16. [PubMed] [Google Scholar]
  56. Zheng C. F., Guan K. L. Properties of MEKs, the kinases that phosphorylate and activate the extracellular signal-regulated kinases. J Biol Chem. 1993 Nov 15;268(32):23933–23939. [PubMed] [Google Scholar]
  57. de Vries-Smits A. M., Burgering B. M., Leevers S. J., Marshall C. J., Bos J. L. Involvement of p21ras in activation of extracellular signal-regulated kinase 2. Nature. 1992 Jun 18;357(6379):602–604. doi: 10.1038/357602a0. [DOI] [PubMed] [Google Scholar]
  58. van Corven E. J., Hordijk P. L., Medema R. H., Bos J. L., Moolenaar W. H. Pertussis toxin-sensitive activation of p21ras by G protein-coupled receptor agonists in fibroblasts. Proc Natl Acad Sci U S A. 1993 Feb 15;90(4):1257–1261. doi: 10.1073/pnas.90.4.1257. [DOI] [PMC free article] [PubMed] [Google Scholar]

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