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Gene Review

FUS3  -  mitogen-activated serine/threonine-protein...

Saccharomyces cerevisiae S288c

Synonyms: DAC2, MAP kinase FUS3, Mitogen-activated protein kinase FUS3, YBL016W, YBL03.21, ...
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Disease relevance of FUS3

  • FUS3 has a positive role in conjugation, because overexpression of FUS3 increases the pheromone sensitivity of wild-type cells, while the absence of FUS3 causes sterility [1].
  • We have isolated dominant gain-of-function (gf) mutations in FUS3, a Saccharomyces cerevisiae mitogen-activated protein (MAP) kinase homolog, that constitutively activate the yeast mating signal transduction pathway and confer hypersensitivity to mating pheromone [2].
  • The presence of the interacting N1-Fus3p adapter increased the infectivity of Ste7p-N2-CT phages approximately 1400-fold, which makes SIP a promising technology for the detection and further investigation of interacting proteins [3].

High impact information on FUS3

  • Notably, mutation of the phosphoacceptor site in Tec1, deletion of FUS3, or deletion of DIA2 results in a loss of signaling specificity such that pheromone pathway signaling erroneously activates filamentation pathway gene expression and invasive growth [4].
  • T273 in a predicted high-affinity Cdc4 binding motif is phosphorylated by Fus3 both in vitro and in vivo [5].
  • Degradation requires Fus3 kinase activity and a MAPK phosphorylation site in Tec1 at threonine 273 [4].
  • Fus3 but not Kss1 induces Tec1 ubiquination and degradation through the SCFCdc4 ubiquitin ligase [5].
  • In the absence of Fus3, there is erroneous crosstalk in which mating pheromone now activates filamentation-specific gene expression using the Kss1 MAPK [6].

Biological context of FUS3

  • The suppression of a gpa1 null (G alpha subunit) by a fus3 null also suggests FUS3 is in the signal transduction pathway [1].
  • FUS3 encodes a cdc2+/CDC28-related kinase required for the transition from mitosis into conjugation [1].
  • This functional redundancy is strain dependent; some standard laboratory strains (S288C) are kss1-. FUS3 has additional functions required for cell cycle arrest and vegetative growth that do not overlap with KSS1 functions [7].
  • Yeast homolog of mammalian mitogen-activated protein kinase, FUS3/DAC2 kinase, is required both for cell fusion and for G1 arrest of the cell cycle and morphological changes by the cdc37 mutation [8].
  • In contrast, disruption of PTP3 in combination with its homolog PTP2 results in constitutive tyrosine phosphorylation, enhanced kinase activity of Fus3p MAP kinase on stimulation, and delayed recovery from the cell cycle arrest [9].

Anatomical context of FUS3

  • After pheromone treatment, Bni1p-GFP and Spa2p failed to localize to the cortex of fus3 mutants, and cell wall growth became completely unpolarized [10].
  • Ste5p remains stably bound at the plasma membrane, unlike activated Fus3p, which dissociates from Ste5p and translocates to the nucleus [11].
  • In support of this possibility, we find that Fus3 is activated to a greater extent in a "wimp" strain with defective protein kinase A. Finally, BIM1 and BIK1 have been identified as CEN suppressors of far5, suggesting that the microtubule apparatus may regulate the ability of the pheromone response pathway to promote G1 arrest [12].

Associations of FUS3 with chemical compounds

  • A FUS3 allele whose gene product is resistant to the HOG-mediated repression of its phosphotyrosine content has been isolated [13].
  • These results suggest that the Arabidopsis cDNA encodes a putative serine/threonine kinase that can function in the mating response pathway upstream of FUS3/KSS1 in S. cerevisiae, at the level of STE11 gene [14].
  • Ste5 copurifies with Ste11, Fus3, and a hypophosphorylated form of Ste7, and all four proteins cosediment in a glycerol gradient as if in a large complex [15].
  • Here we show that expression of the guanine nucleotide exchange factor for Cdc42 SopE2 in Saccharomyces cerevisiae leads to the activation of Fus3 and Kss1 MAPKs, which operate in the mating and filamentation pathways, causing filamentous growth in haploid yeast cells [16].

Physical interactions of FUS3

  • We also found that both Ste11p and Ste7p interact with Fus3p and Kss1p [17].
  • Relative to Kss1, the MAPK Fus3 binds less strongly to Ste12 and is correspondingly a weaker inhibitor of invasive growth [18].

Enzymatic interactions of FUS3

  • Ptp3p directly dephosphorylates and inactivates Fus3p MAP kinase in vitro [9].
  • Fourth Ste5 is phosphorylated by Fus3 in purified complexes and copurifies with an additional protein kinase(s) [19].
  • FUS3 and presumably KSS1 are phosphorylated and activated during pheromone induction by a STE7-dependent mechanism [20].
  • We present evidence that, during mating, Fus3 phosphorylates Tec1 to downregulate this invasive growth-specific transcription factor and its target genes [21].

Regulatory relationships of FUS3

  • CLN2 overexpression represses Fus3 kinase activity, independently of the phosphatase Msg5 [22].
  • The dac2 mutation could suppress the lethality caused by the disruption of the GPA1 gene (previously shown to encode a protein with similarity to the alpha subunit of mammalian G proteins) [23].
  • These observations suggest the possibility that Ste5 promotes signal transduction by tethering Fus3 to its activating protein kinase(s) [19].
  • MAP kinase-related FUS3 from S. cerevisiae is activated by STE7 in vitro [24].
  • Thus MSG5 might stimulate recovery from pheromone by regulating the phosphorylation state of FUS3 [25].

Other interactions of FUS3

  • The predicted FUS3 protein is 35% identical to the cdc2+/CDC28 kinases and 52% identical to the KSS1 predicted kinase [1].
  • The predicted Mpk1 protein (Mpk1p) shares 48 to 50% sequence identity with Xenopus MAP kinase and with the yeast mating pheromone response pathway components, Fus3p and Kss1p [26].
  • Neither protein altered the ability of the mitogen-activated protein kinase (MAPK) Fus3 to feedback phosphorylate a known substrate, the MAPK kinase Ste7 [27].
  • These data support a model in which FUS3 mediates transcription and G1 arrest by direct activation of STE12 and FAR1 and phosphorylates many other proteins involved in the response to pheromone [28].
  • We find that Fus3p and Kss1p both control G1 arrest through multiple functions that operate in parallel with Far1p [29].

Analytical, diagnostic and therapeutic context of FUS3


  1. FUS3 encodes a cdc2+/CDC28-related kinase required for the transition from mitosis into conjugation. Elion, E.A., Grisafi, P.L., Fink, G.R. Cell (1990) [Pubmed]
  2. A role for autophosphorylation revealed by activated alleles of FUS3, the yeast MAP kinase homolog. Brill, J.A., Elion, E.A., Fink, G.R. Mol. Biol. Cell (1994) [Pubmed]
  3. In vivo selectively infective phage as a tool to detect protein interactions: evaluation of a novel vector system with yeast Ste7p-Fus3p interacting proteins. Hertveldt, K., Robben, J., Volckaert, G. Yeast (2002) [Pubmed]
  4. Pheromone-dependent destruction of the Tec1 transcription factor is required for MAP kinase signaling specificity in yeast. Bao, M.Z., Schwartz, M.A., Cantin, G.T., Yates, J.R., Madhani, H.D. Cell (2004) [Pubmed]
  5. Fus3-regulated Tec1 degradation through SCFCdc4 determines MAPK signaling specificity during mating in yeast. Chou, S., Huang, L., Liu, H. Cell (2004) [Pubmed]
  6. MAP kinases with distinct inhibitory functions impart signaling specificity during yeast differentiation. Madhani, H.D., Styles, C.A., Fink, G.R. Cell (1997) [Pubmed]
  7. FUS3 represses CLN1 and CLN2 and in concert with KSS1 promotes signal transduction. Elion, E.A., Brill, J.A., Fink, G.R. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  8. Yeast homolog of mammalian mitogen-activated protein kinase, FUS3/DAC2 kinase, is required both for cell fusion and for G1 arrest of the cell cycle and morphological changes by the cdc37 mutation. Fujimura, H.A. J. Cell. Sci. (1994) [Pubmed]
  9. Differential regulation of FUS3 MAP kinase by tyrosine-specific phosphatases PTP2/PTP3 and dual-specificity phosphatase MSG5 in Saccharomyces cerevisiae. Zhan, X.L., Deschenes, R.J., Guan, K.L. Genes Dev. (1997) [Pubmed]
  10. Pheromone-induced polarization is dependent on the Fus3p MAPK acting through the formin Bni1p. Matheos, D., Metodiev, M., Muller, E., Stone, D., Rose, M.D. J. Cell Biol. (2004) [Pubmed]
  11. MAP kinase dynamics in response to pheromones in budding yeast. van Drogen, F., Stucke, V.M., Jorritsma, G., Peter, M. Nat. Cell Biol. (2001) [Pubmed]
  12. far4, far5, and far6 define three genes required for efficient activation of MAPKs Fus3 and Kss1 and accumulation of glycogen. Cherkasova, V., Elion, E.A. Curr. Genet. (2001) [Pubmed]
  13. The osmoregulatory pathway represses mating pathway activity in Saccharomyces cerevisiae: isolation of a FUS3 mutant that is insensitive to the repression mechanism. Hall, J.P., Cherkasova, V., Elion, E., Gustin, M.C., Winter, E. Mol. Cell. Biol. (1996) [Pubmed]
  14. Arabidopsis thaliana cDNA isolated by functional complementation shows homology to serine/threonine protein kinases. Covic, L., Lew, R.R. Biochim. Biophys. Acta (1996) [Pubmed]
  15. Ste5 tethers multiple protein kinases in the MAP kinase cascade required for mating in S. cerevisiae. Choi, K.Y., Satterberg, B., Lyons, D.M., Elion, E.A. Cell (1994) [Pubmed]
  16. A novel connection between the yeast Cdc42 GTPase and the Slt2-mediated cell integrity pathway identified through the effect of secreted Salmonella GTPase modulators. Rodríguez-Pachón, J.M., Martín, H., North, G., Rotger, R., Nombela, C., Molina, M. J. Biol. Chem. (2002) [Pubmed]
  17. Protein-protein interactions in the yeast pheromone response pathway: Ste5p interacts with all members of the MAP kinase cascade. Printen, J.A., Sprague, G.F. Genetics (1994) [Pubmed]
  18. Repression of yeast Ste12 transcription factor by direct binding of unphosphorylated Kss1 MAPK and its regulation by the Ste7 MEK. Bardwell, L., Cook, J.G., Voora, D., Baggott, D.M., Martinez, A.R., Thorner, J. Genes Dev. (1998) [Pubmed]
  19. The MAP kinase Fus3 associates with and phosphorylates the upstream signaling component Ste5. Kranz, J.E., Satterberg, B., Elion, E.A. Genes Dev. (1994) [Pubmed]
  20. Pheromone-induced signal transduction in Saccharomyces cerevisiae requires the sequential function of three protein kinases. Zhou, Z., Gartner, A., Cade, R., Ammerer, G., Errede, B. Mol. Cell. Biol. (1993) [Pubmed]
  21. Differential regulation of Tec1 by Fus3 and Kss1 confers signaling specificity in yeast development. Brückner, S., Köhler, T., Braus, G.H., Heise, B., Bolte, M., Mösch, H.U. Curr. Genet. (2004) [Pubmed]
  22. Overexpression of the G1-cyclin gene CLN2 represses the mating pathway in Saccharomyces cerevisiae at the level of the MEKK Ste11. Wassmann, K., Ammerer, G. J. Biol. Chem. (1997) [Pubmed]
  23. Identification and characterization of a mutation affecting the division arrest signaling of the pheromone response pathway in Saccharomyces cerevisiae. Fujimura, H. Genetics (1990) [Pubmed]
  24. MAP kinase-related FUS3 from S. cerevisiae is activated by STE7 in vitro. Errede, B., Gartner, A., Zhou, Z., Nasmyth, K., Ammerer, G. Nature (1993) [Pubmed]
  25. MSG5, a novel protein phosphatase promotes adaptation to pheromone response in S. cerevisiae. Doi, K., Gartner, A., Ammerer, G., Errede, B., Shinkawa, H., Sugimoto, K., Matsumoto, K. EMBO J. (1994) [Pubmed]
  26. A yeast mitogen-activated protein kinase homolog (Mpk1p) mediates signalling by protein kinase C. Lee, K.S., Irie, K., Gotoh, Y., Watanabe, Y., Araki, H., Nishida, E., Matsumoto, K., Levin, D.E. Mol. Cell. Biol. (1993) [Pubmed]
  27. Identification of novel pheromone-response regulators through systematic overexpression of 120 protein kinases in yeast. Burchett, S.A., Scott, A., Errede, B., Dohlman, H.G. J. Biol. Chem. (2001) [Pubmed]
  28. FUS3 phosphorylates multiple components of the mating signal transduction cascade: evidence for STE12 and FAR1. Elion, E.A., Satterberg, B., Kranz, J.E. Mol. Biol. Cell (1993) [Pubmed]
  29. Fus3p and Kss1p control G1 arrest in Saccharomyces cerevisiae through a balance of distinct arrest and proliferative functions that operate in parallel with Far1p. Cherkasova, V., Lyons, D.M., Elion, E.A. Genetics (1999) [Pubmed]
  30. Characterization of Fus3 localization: active Fus3 localizes in complexes of varying size and specific activity. Choi, K.Y., Kranz, J.E., Mahanty, S.K., Park, K.S., Elion, E.A. Mol. Biol. Cell (1999) [Pubmed]
  31. Molecular cloning of the DAC2/FUS3 gene essential for pheromone-induced G1-arrest of the cell cycle in Saccharomyces cerevisiae. Fujimura, H. Curr. Genet. (1990) [Pubmed]
  32. Histone deacetylases in Trypanosoma brucei: two are essential and another is required for normal cell cycle progression. Ingram, A.K., Horn, D. Mol. Microbiol. (2002) [Pubmed]
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