Department of
Biological Chemistry & Molecular Pharmacology

Elaine Elion

Professor
Telephone: 
617-432-3815
Fax: 
617-738-0516
Address: 
Room C1-302
Address: 
240 Longwood Avenue
Address: 
Boston MA 02115
Research Areas

Our group studies eukaryotic signal transduction, focusing on how external stimuli control proliferation, differentiation, and homeostasis. Work has centered on defining how mitogen activated protein kinase (MAPK) cascades function in vivo. MAPK cascades form the cores of numerous eukaryotic signal transduction pathways that control growth, differentiation and survival. Misregulation of MAPK cascades is associated with a variety of diseases, including cancer. We use a yeast model system (Figure 1) and genetic, biochemical and cell biological approaches.

Figure 1.

Figure 1. Saccharomyces cerevisiae is regulated by multiple MAPKs which perform distinct functions by phosphorylating distinct protein that control growth and differentiation.

How does a scaffold protein regulate the activity of a signal MAPK cascade? Scaffold proteins are known to regulate numerous signal transduction pathways in eukaryotic cells. The first MAPK cascade scaffold to be characterized was Ste5, which regulates the Saccharomyces cerevisiae mating MAPK cascade. It is called Ste5, because mutations in the STE5 gene cause sterility and block yeast mating. Ste5 is a dynamic protein that shuttles through the nucleus, binds many different proteins, and is essential for activation of a MAPK cascade (Figure 2).

Figure 2. The Ste5 scaffold tethers components of a MAPK cascade and links the MAPKKK Ste11 to the Ste20 kinase at the plasma membrane through an interaction with the b subunit of a heterotrimeric G protein. Some of these kinases also act in other pathways.Figure 2. The Ste5 scaffold tethers components of a MAPK cascade and links the MAPKKK Ste11 to the Ste20 kinase at the plasma membrane through an interaction with the b subunit of a heterotrimeric G protein. Some of these kinases also act in other pathways.

Little is known about how a MAPK scaffold regulates MAPK activity. We are interested in understanding how the scaffold binds various signaling components and how oligomerization of the scaffold relates to its activity and localization in the nucleus, cytoplasm and plasma membrane and association with signaling components that are differentially distributed in these cellular compartments. We are determining the biological rationale for nuclear shuttling as a priming event for plasma membrane recruitment and are identifying the factors involved in this event. We are also studying how a scaffold/ MAPK complex is properly assembled at the plasma membrane and the physiological importance of stable recruitment by identifying gene products that are required for recruitment and links between the scaffold and regulators of polarized growth. An example of a regulator is shown in Figure 3.

Figure 3. A specialized cytoskeletal machinery headed by the Bni1 formin recruits MAPK scaffold Ste5 to sites of polarized growth via actin cables.Figure 3. A specialized cytoskeletal machinery headed by the Bni1 formin recruits MAPK scaffold Ste5 to sites of polarized growth via actin cables.

2. Homeostatic mechanisms regulating MAPK activation. Heightened activation of MAPK cascades are implicated in a wide variety of disease states, with the physiological outcome varying in different cell types. The basal activity of a MAPK cascade is a critical determinant of pathway outcome and the level of stimulus required to induce a particular response. We are identifying regulators of basal signaling that determine the set point of MAPK cascades. In addition, we are characterizing how a key phosphatase acts as a specificity factor to control two alternative fates of a single MAPK cascade.

3. MAPK cascade cross-regulates Ras/cAMP signaling, survival and apoptosis. We have discovered a novel regulatory link between a MAPK cascade and yeast Ras that is essential for survival. We are studying how this circuitry operates and the generality of this mode of control. In addition, we characterizing apoptosis in yeast and have defined mitochondrial -independent pathways that promote apoptosis. Through genetic screens we have identified genes and mutations that enhance apoptosis and are studying how they induce death ( Figure 4 ).

Figure 4.

Publications: 
  1. Elion EA. MAP Kinase Modules in Signaling, Biomedical Sciences - Cancer and Endocrine Diseases, Michael Caplan, editor. Elsevier, Inc., Waltham, MA in press. 2015.  
  2. Wang X, Sheff MA, Simpson DM, Elion EA. Ste11p MEKK signals through HOG, mating, calcineurin and PKC pathways to regulate the FKS2 gene. BMC Mol Biol. 2011; 12:51. View in: PubMed
  3. Elion EA, Sahoo R. Analysis of mitogen-activated protein kinase activity in yeast. Methods Mol Biol. 2010; 661:387-99. View in: PubMed
  4. Yu L, Qi M, Sheff MA, Elion EA. Counteractive control of polarized morphogenesis during mating by mitogen-activated protein kinase Fus3 and G1 cyclin-dependent kinase. Mol Biol Cell. 2008 Apr; 19(4):1739-52. View in: PubMed
  5. Sahoo R, Husain A and Elion EA. MAP kinase in yeast. Handbook of Cellular Signaling, Bradshaw R. and Dennis E, editors, T. Hunter T and Scott JD, associate editors. Academic Press. 2008.  
  6. Elion EA. Detection of protein-protein interactions by coprecipitation. Curr Protoc Protein Sci. 2007 Aug; Chapter 19:Unit 19.4. View in: PubMed
  7. Elion EA, Marina P, Yu L. Constructing recombinant DNA molecules by PCR. Curr Protoc Mol Biol. 2007 Apr; Chapter 3:Unit 3.17. View in: PubMed
  8. Elion EA. Detection of protein-protein interactions by coprecipitation. Curr Protoc Immunol. 2007 Feb; Chapter 8:Unit 8.7. View in: PubMed
  9. Elion EA. Methods for analyzing MAPK cascades. Methods. 2006 Nov; 40(3):207-8. View in: PubMed
  10. Elion EA. Detection of protein-protein interactions by coprecipitation. Curr Protoc Mol Biol. 2006 Nov; Chapter 20:Unit20.5. View in: PubMed
  11. Elion EA. Detection of protein-protein interactions by coprecipitation. Curr Protoc Neurosci. 2006 May; Chapter 5:Unit 5.25. View in: PubMed
  12. Qi M, Elion EA. MAP kinase pathways. J Cell Sci. 2005 Aug 15; 118(Pt 16):3569-72. View in: PubMed
  13. Qi M, Elion EA. Formin-induced actin cables are required for polarized recruitment of the Ste5 scaffold and high level activation of MAPK Fus3. J Cell Sci. 2005 Jul 1; 118(Pt 13):2837-48. View in: PubMed
  14. Elion EA, Qi M, Chen W. Signal transduction. Signaling specificity in yeast. Science. 2005 Feb 4; 307(5710):687-8. View in: PubMed
  15. Wang Y, Chen W, Simpson DM, Elion EA. Cdc24 regulates nuclear shuttling and recruitment of the Ste5 scaffold to a heterotrimeric G protein in Saccharomyces cerevisiae. J Biol Chem. 2005 Apr 1; 280(13):13084-96. View in: PubMed
  16. Flotho A, Simpson DM, Qi M, Elion EA. Localized feedback phosphorylation of Ste5p scaffold by associated MAPK cascade. J Biol Chem. 2004 Nov 5; 279(45):47391-401. View in: PubMed
  17. Andersson J, Simpson DM, Qi M, Wang Y, Elion EA. Differential input by Ste5 scaffold and Msg5 phosphatase route a MAPK cascade to multiple outcomes. EMBO J. 2004 Jul 7; 23(13):2564-76. View in: PubMed
  18. Elion EA, Wang Y. Making protein immunoprecipitates. Methods Mol Biol. 2004; 284:1-14. View in: PubMed
  19. Elion EA. Co-precipitating proteins. For: Signal Transduction Protocols in Methods in Molecular Biology, R.C. Dickson RC and Mendenhall MD, editors. Human Press. 2004.  
  20. Cherkasova VA, McCully R, Wang Y, Hinnebusch A, Elion EA. A novel functional link between MAP kinase cascades and the Ras/cAMP pathway that regulates survival. Curr Biol. 2003 Jul 15; 13(14):1220-6. View in: PubMed
  21. Wang Y, Elion EA. Nuclear export and plasma membrane recruitment of the Ste5 scaffold are coordinated with oligomerization and association with signal transduction components. Mol Biol Cell. 2003 Jun; 14(6):2543-58. View in: PubMed
  22. Elion EA. MAP kinase in yeast. Handbook of Cellular Signaling, Bradshaw R. and Dennis E, editors, T. Hunter T and Scott JD, associate editors. Academic Press. 2003.  
  23. Cherkasova V McCully R Wang Y Hinnebusch A and Elion EA. . A novel functional link between MAPKs and the Ras/cAMP pathway required for survival. Current Biology. 2003; (13):1214-1219.  
  24. Elion EA. MAP Kinase Modules in Signaling; Encyclopedia of Cancer, Second Edition I. Biology of Cancer, Wang J, editor. San Diego, California: Academic Press. 2002.  
  25. Elion EA. How to monitor nuclear shuttling. Methods Enzymol. 2002; 351:607-22. View in: PubMed
  26. Elion EA. The Ste5p scaffold. J Cell Sci. 2001 Nov; 114(Pt 22):3967-78. View in: PubMed
  27. Cherkasova V, Elion EA. far4, far5, and far6 define three genes required for efficient activation of MAPKs Fus3 and Kss1 and accumulation of glycogen. Curr Genet. 2001 Aug; 40(1):13-26. View in: PubMed
  28. Elion EA. Pheromone response, mating and cell biology. Curr Opin Microbiol. 2000 Dec; 3(6):573-81. View in: PubMed
  29. Elion EA. Co-precipitating proteins. Current Protocols in Molecular Biology, Ausubel,F, Brent R Kingston R, Moore D, Smith JA, Seidman J, Struhl K, editors.. Guilford, CT: Greene Publishing Associates and Wiley. 2000.  
  30. Lee BN, Elion EA. The MAPKKK Ste11 regulates vegetative growth through a kinase cascade of shared signaling components. Proc Natl Acad Sci U S A. 1999 Oct 26; 96(22):12679-84. View in: PubMed
  31. Mahanty SK, Wang Y, Farley FW, Elion EA. Nuclear shuttling of yeast scaffold Ste5 is required for its recruitment to the plasma membrane and activation of the mating MAPK cascade. Cell. 1999 Aug 20; 98(4):501-12. View in: PubMed
  32. Choi KY, Kranz JE, Mahanty SK, Park KS, Elion EA. Characterization of Fus3 localization: active Fus3 localizes in complexes of varying size and specific activity. Mol Biol Cell. 1999 May; 10(5):1553-68. View in: PubMed
  33. Farley FW, Satterberg B, Goldsmith EJ, Elion EA. Relative dependence of different outputs of the Saccharomyces cerevisiae pheromone response pathway on the MAP kinase Fus3p. Genetics. 1999 Apr; 151(4):1425-44. View in: PubMed
  34. Cherkasova V, Lyons DM, Elion EA. Fus3p and Kss1p control G1 arrest in Saccharomyces cerevisiae through a balance of distinct arrest and proliferative functions that operate in parallel with Far1p. Genetics. 1999 Mar; 151(3):989-1004. View in: PubMed
  35. Leza MA, Elion EA. POG1, a novel yeast gene, promotes recovery from pheromone arrest via the G1 cyclin CLN2. Genetics. 1999 Feb; 151(2):531-43. View in: PubMed
  36. Elion EA. Routing MAP kinase cascades. Science. 1998 Sep 11; 281(5383):1625-6. View in: PubMed
  37. Feng Y, Song LY, Kincaid E, Mahanty SK, Elion EA. Functional binding between Gbeta and the LIM domain of Ste5 is required to activate the MEKK Ste11. Curr Biol. 1998 Feb 26; 8(5):267-78. View in: PubMed
  38. Hall JP, Cherkasova V, Elion E, Gustin MC, Winter E. The osmoregulatory pathway represses mating pathway activity in Saccharomyces cerevisiae: isolation of a FUS3 mutant that is insensitive to the repression mechanism. Mol Cell Biol. 1996 Dec; 16(12):6715-23. View in: PubMed
  39. Lyons DM, Mahanty SK, Choi KY, Manandhar M, Elion EA. The SH3-domain protein Bem1 coordinates mitogen-activated protein kinase cascade activation with cell cycle control in Saccharomyces cerevisiae. Mol Cell Biol. 1996 Aug; 16(8):4095-106. View in: PubMed
  40. Elion EA, Trueheart J, Fink GR. Fus2 localizes near the site of cell fusion and is required for both cell fusion and nuclear alignment during zygote formation. J Cell Biol. 1995 Sep; 130(6):1283-96. View in: PubMed
  41. Elion EA. Ste5: a meeting place for MAP kinases and their associates. Trends Cell Biol. 1995 Aug; 5(8):322-7. View in: PubMed
  42. Elion EA. . Using the polymerase chain reaction to construct recombinant DNA molecules (Unit 3.17) In: Current Protocols in Molecular Biology, Ausubel,F, Brent R Kingston R, Moore D, Smith JA, Seidman J, Struhl K, editors.. Guilford, CT: Greene Publishing Associates and Wiley. 1995.  
  43. Choi KY, Satterberg B, Lyons DM, Elion EA. Ste5 tethers multiple protein kinases in the MAP kinase cascade required for mating in S. cerevisiae. Cell. 1994 Aug 12; 78(3):499-512. View in: PubMed
  44. Brill JA, Elion EA, Fink GR. A role for autophosphorylation revealed by activated alleles of FUS3, the yeast MAP kinase homolog. Mol Biol Cell. 1994 Mar; 5(3):297-312. View in: PubMed
  45. Kranz JE, Satterberg B, Elion EA. The MAP kinase Fus3 associates with and phosphorylates the upstream signaling component Ste5. Genes Dev. 1994 Feb 1; 8(3):313-27. View in: PubMed
  46. Elion EA, Satterberg B, Kranz JE. FUS3 phosphorylates multiple components of the mating signal transduction cascade: evidence for STE12 and FAR1. Mol Biol Cell. 1993 May; 4(5):495-510. View in: PubMed
  47. Elion EA, Brill JA, Fink GR. FUS3 represses CLN1 and CLN2 and in concert with KSS1 promotes signal transduction. Proc Natl Acad Sci U S A. 1991 Nov 1; 88(21):9392-6. View in: PubMed
  48. Elion EA, Brill JA, Fink GR. Functional redundancy in the yeast cell cycle: FUS3 and KSS1 have both overlapping and unique functions. Cold Spring Harb Symp Quant Biol. 1991; 56:41-9. View in: PubMed
  49. Elion EA, Grisafi PL, Fink GR. FUS3 encodes a cdc2+/CDC28-related kinase required for the transition from mitosis into conjugation. Cell. 1990 Feb 23; 60(4):649-64. View in: PubMed
  50. Warner J R, Elion E A, Dabeva M D, and Schwindinger WF. The ribosomal genes of yeast and their regulation. Ribosomes: Genetics, Structure and Function. 1988.  
  51. Elion EA and Fink GR. FUS3. In: Protein Kinase Factsbook, Hanks S and Hardie DG, editors, Academic Press. 1988.  
  52. Elion EA, Warner JR. An RNA polymerase I enhancer in Saccharomyces cerevisiae. Mol Cell Biol. 1986 Jun; 6(6):2089-97. View in: PubMed
  53. Elion EA and Warner JR. Sequence Specificty in Transcription and Translation, UCLA Symposia on Molecular and Cellular Biology, New Series, Calendar R and Gold L, editors. Functional elements of the yeast rRNA transcription uni. 1985; 30.  
  54. Elion EA and Warner JR. Characterization of a yeast RNA polymerase I enhancer. Transcriptional Control Mechanisms, UCLA Symposia on Molecular and Cellular Biology, New Series, Volume 52, Granner DK, Rosenfeld G and Chang S, editors. 1985.  
  55. Elion EA, Warner JR. The major promoter element of rRNA transcription in yeast lies 2 kb upstream. Cell. 1984 Dec; 39(3 Pt 2):663-73. View in: PubMed
  56. Fillit H, Elion E, Sullivan J, Sherman R, Zabriskie JB. Thiobarbituric acid reactive material in uremic blood. Nephron. 1981; 29(1-2):40-3. View in: PubMed
  57. Elion EA and Wang YM. Making protein immunoprecipitates. Methods in Molecular Biology 2004; 284: 1-14.

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