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The role of adaptor protein Ste50-dependent regulation of the MAPKKK Ste11 in multiple signalling pathways of yeast

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Abstract

In Saccharomyces cerevisiae, Ste50 functions in cell signalling between the activated G protein and the mitogen-activated protein kinase (MAPK) kinase kinase (MAPKKK) Ste11. ScSte50 is an essential component of three MAPK-mediated signalling pathways, which control the mating response, invasive/filamentous growth and osmotolerance (HOG pathway), respectively. ScSte50 signalling may also contribute to cell wall integrity in vegetative cells. The protein contains a sterile alpha motif (SAM) and a putative Ras-associated domain (RAD), which are essential for signal transduction. Ste50 and Ste11 interact constitutively via their SAM regions. Ste50 interacts weakly and probably transiently with the pheromone receptor-bound heterotrimeric G protein Gαβγ, and with the small G proteins Cdc42, Ras1 and Ras2. It is specifically the RAD region of Ste50 that mediates the interactions with Cdc42 and Ras. Homologues of ScSTE50 are also found in other fungi, like S. kluyveri, Hansenula polymorpha, Candida albicans and Neurospora crassa. In this review, the role of Ste50 as an adaptor that links the G protein-associated Cdc42-Ste20 kinase complex to the effector kinase Ste11 and thus modulates signal transduction, especially in the pheromone-response pathway of S. cerevisiae, is discussed.

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References

  • Barr MM, Tu H, Aelst L van, Wigler M (1996) Identification of Ste4 as a potential regulator of Byr2 in the sexual response pathway of Schizosaccharomyces pombe. Mol Cell Biol 16:5597–5603

    CAS  PubMed  Google Scholar 

  • Bidlingmaier S, Weiss EL, Seidel C, Drubin DG, Snyder M (2001) The Cbk1p pathway is important for polarized cell growth and cell separation in Saccharomyces cerevisiae. Mol Cell Biol 21:2449–2462

    CAS  PubMed  Google Scholar 

  • Breitkreutz A, Tyers M (2002) MAPK signaling specificity: it takes two to tango. Trends Cell Biol 12:254–257

    Article  CAS  PubMed  Google Scholar 

  • Brewster JL, Valoir T de, Dwyer ND, Winter E, Gustin MC (1993) An osmosensing signal transduction pathway in yeast. Science 259:1760–1763

    CAS  PubMed  Google Scholar 

  • Choi KY, Satterberg B, Lyons DM, Elion EA (1994) Ste5 tethers multiple protein kinases in the MAP kinase cascade required for mating in S. cerevisiae. Cell 78:499–512

    CAS  PubMed  Google Scholar 

  • Cliften PF, Hillier LW, Fulton L, Graves T, Miner T, Gish WR, Waterston RH, Johnston M (2001) Surveying Saccharomyces genomes to identify functional elements by comparative DNA sequence analysis. Genome Res 11:1175–1186

    Article  CAS  PubMed  Google Scholar 

  • Colman-Lerner A, Chin TE, Brent R (2001)Yeast Cbk1 and Mob2 activate daughter-specific genetic programs to induce asymmetric cell fates. Cell 107:739–750

    CAS  PubMed  Google Scholar 

  • Cullen PJ, Schultz J, Horecka J, Stevenson BJ, Jigami Y, Sprague GF Jr (2000) Defects in protein glycosylation cause SHO1-dependent activation of a STE12 signaling pathway in yeast. Genetics 155:1005–1018

    CAS  PubMed  Google Scholar 

  • Dohlman HG, Thorner JW (2001) Regulation of G protein-initiated signal transduction in yeast: paradigms and principles. Annu Rev Biochem 70:703–754

    Article  CAS  PubMed  Google Scholar 

  • Drogen F van, Peter M (2002) MAP kinase cascades: scaffolding signal specificity. Curr Biol 12:R53–R55

    PubMed  Google Scholar 

  • Drogen F van, O'Rourke SM, Stucke VM, Jaquenoud M, Neiman AM, Peter M (2000) Phosphorylation of the MEKK Ste11p by the PAK-like kinase Ste20p is required for MAP kinase signaling in vivo. Curr Biol 10:630–639

    Article  CAS  PubMed  Google Scholar 

  • Elion EA (2000) Pheromone response, mating and cell biology. Curr Opin Microbiol 3:573–581

    CAS  PubMed  Google Scholar 

  • Elion EA (2001) The Ste5p scaffold. J Cell Sci 114:3967–3978

    CAS  PubMed  Google Scholar 

  • Errede B, Ge QY (1996) Feedback regulation of MAP kinase signal pathways. Philos Trans R Soc Lond B Biol Sci 351:143–149

    CAS  PubMed  Google Scholar 

  • Esch RK, Errede B (2002) Pheromone induction promotes Ste11 degradation through a MAPK feedback and ubiquitin-dependent mechanism. Proc Natl Acad Sci USA 99:9160–165

    Article  CAS  PubMed  Google Scholar 

  • Feng Y, Song LY, Kincaid E, Mahanty SK, Elion EA (1998) Functional binding between Gbeta and the LIM domain of Ste5 is required to activate the MEKK Ste11. Curr Biol 8:267–278

    CAS  PubMed  Google Scholar 

  • Geyer CR, Colman-Lerner A, Brent R (1999) "Mutagenesis" by peptide aptamers identifies genetic network members and pathway connections. Proc Natl Acad Sci USA 96:8567–8572

    CAS  PubMed  Google Scholar 

  • Gimeno CJ, Ljungdahl PO, Styles CA, Fink GR (1992) Unipolar cell divisions in the yeast S. cerevisiae lead to filamentous growth: regulation by starvation and RAS. Cell 68:1077–1090

    PubMed  Google Scholar 

  • Goffeau A, Barrell BG, Bussey H, Davis RW, Dujon B, Feldmann H, Galibert F, Hoheisel JD, Jacq C, Johnston M, Louis EJ, Mewes HW, Murakami Y, Philippsen P, Tettelin H, Oliver SG (1996) Life with 6000 genes. Science 274:546, 563–567

    CAS  PubMed  Google Scholar 

  • Gustin MC, Albertyn J, Alexander M, Davenport K (1998) MAP kinase pathways in the yeast Saccharomyces cerevisiae. Microbiol Mol Biol Rev 62:1264–1300

    CAS  PubMed  Google Scholar 

  • Harris K, Lamson RE, Nelson B, Hughes TR, Marton MJ, Roberts CJ, Boone C, Pryciak PM (2001) Role of scaffolds in MAP kinase pathway specificity revealed by custom design of pathway-dedicated signaling proteins. Curr Biol 11:1815–1824

    CAS  PubMed  Google Scholar 

  • Herrmann C, Horn G, Spaargaren M, Wittinghofer A (1996) Differential interaction of the Ras family GTP-binding proteins H-Ras, Rap1A, and R-Ras with the putative effector molecules Raf kinase and Ral-guanine nucleotide exchange factor. J Biol Chem 271:6794–6800

    Article  CAS  PubMed  Google Scholar 

  • Hohmann S (2002) Osmotic stress signaling and osmoadaptation in yeasts. Microbiol Mol Biol Rev 66:300–372

    CAS  PubMed  Google Scholar 

  • Inouye C, Dhillon N, Thorner J (1997) Ste5 RING-H2 domain: role in Ste4-promoted oligomerization for yeast pheromone signaling. Science 278:103–106

    Article  CAS  PubMed  Google Scholar 

  • Jansen G, Buhring F, Hollenberg CP, Ramezani Rad M (2001) Mutations in the SAM domain of STE50 differentially influence the MAPK-mediated pathways for mating, filamentous growth and osmotolerance in Saccharomyces cerevisiae. Mol Genet Genomics 265:102–117

    Article  CAS  PubMed  Google Scholar 

  • Kido M, Shima F, Satoh T, Asato T, Kariya K, Kataoka T (2002) Critical function of the Ras-associating domain as a primary Ras-binding site for regulation of Saccharomyces cerevisiae adenylyl cyclase. J Biol Chem 277:3117–3123

    Article  CAS  PubMed  Google Scholar 

  • Kyba M, Brock HW (1998) The SAM domain of polyhomeotic, RAE28, and Scm mediates specific interactions through conserved residues. Dev Genet 22:74–84

    Article  CAS  PubMed  Google Scholar 

  • Lamson RE, Winters MJ, Pryciak PM (2002) Cdc42 regulation of kinase activity and signaling by the yeast p21-activated kinase Ste20. Mol Cell Biol 22:2939–2951

    Article  CAS  PubMed  Google Scholar 

  • Leberer E, Thomas DY, Whiteway M (1997a) Pheromone signalling and polarised morphogenesis in yeast. Curr Opin Genet Dev 7:59–66

    CAS  PubMed  Google Scholar 

  • Leberer E, Wu C, Leeuw T, Fourest-Lieuvin A, Segall JE, Thomas DY (1997b) Functional characterization of the Cdc42p binding domain of yeast Ste20p protein kinase. EMBO J 16:83–97

    Article  CAS  PubMed  Google Scholar 

  • Lee BN, Elion EA (1999)The MAPKKK Ste11 regulates vegetative growth through a kinase cascade of shared signaling components. Proc Natl Acad Sci USA 96:12679–12684

    Article  CAS  PubMed  Google Scholar 

  • Leeuw T, Fourest-Lieuvin A, Wu C, Chenevert J, Clark K, Whiteway M, Thomas DY, Leberer E (1995) Pheromone response in yeast: association of Bem1p with proteins of the MAP kinase cascade and actin. Science 270:1210–1213

    CAS  PubMed  Google Scholar 

  • Leeuw T, Wu C, Schrag JD, Whiteway M, Thomas DY, Leberer E (1998) Interaction of a G protein β-subunit with a conserved sequence in Ste20/PAK family protein kinases. Nature 391:191–195

    Google Scholar 

  • Madhani HD, Fink GR (1997) Combinatorial control required for the specificity of yeast MAPK signaling. Science 275:1314–1317

    CAS  PubMed  Google Scholar 

  • Madhani HD, Fink GR (1998) The control of filamentous differentiation and virulence in fungi. Trends Cell Biol 8:348–353

    PubMed  Google Scholar 

  • Maeda T, Wurgler-Murphy SM, Saito H (1994) A two-component system that regulates an osmosensing MAP kinase cascade in yeast. Nature 369:242–245

    CAS  PubMed  Google Scholar 

  • Marcus S, Polverino A, Barr M, Wigler M (1994) Complexes between STE5 and components of the pheromone-responsive mitogen-activated protein kinase module. Proc Natl Acad Sci USA 91:7762–7766

    CAS  PubMed  Google Scholar 

  • Mayorga ME, Gold SE (2001) The ubc2 gene of Ustilago maydis encodes a putative novel adaptor protein required for filamentous growth, pheromone response and virulence. Mol Microbiol 41:1365–1379

    Article  CAS  PubMed  Google Scholar 

  • Metodiev MV, Matheos D, Rose MD, Stone DE (2002) Regulation of MAPK function by direct interaction with the mating-specific Galpha in yeast. Science 296:1483–1486

    Article  CAS  PubMed  Google Scholar 

  • Mösch HU, Roberts RL, Fink GR (1996) Ras2 signals via the Cdc42/Ste20/mitogen-activated protein kinase module to induce filamentous growth in Saccharomyces cerevisiae. Proc Natl Acad Sci USA 93:5352–5356

    Article  PubMed  Google Scholar 

  • Moskow JJ, Gladfelter AS, Lamson RE, Pryciak PM, Lew DJ (2000) Role of Cdc42p in pheromone-stimulated signal transduction in Saccharomyces cerevisiae. Mol Cell Biol 20:7559–7571

    Article  CAS  PubMed  Google Scholar 

  • Norman TC, Smith DL, Sorger PK, Drees BL, O'Rourke SM, Hughes TR, Roberts CJ, Friend SH, Fields S, Murray AW (1999) Genetic selection of peptide inhibitors of biological pathways. Science 285:591–595

    Article  CAS  PubMed  Google Scholar 

  • Okazaki N, Okazaki K, Tanaka K, Okayama H (1991) The ste4+ gene, essential for sexual differentiation of Schizosaccharomyces pombe, encodes a protein with a leucine zipper motif. Nucleic Acids Res 19:7043–7047

    CAS  PubMed  Google Scholar 

  • O'Rourke S, Herskowitz I (1998) The HOG1 MAPK prevents cross talk between the HOG and pheromone response MAPK pathway in Saccharomyces cerevisiae. Genes Dev 12:2874–2886

    CAS  PubMed  Google Scholar 

  • O'Rourke SM, Herskowitz I (2002) A third osmosensing branch in Saccharomyces cerevisiae requires the Msb2 protein and functions in parallel with the Sho1 branch. Mol Cell Biol 22:4739–4749

    Article  CAS  PubMed  Google Scholar 

  • O'Rourke SM, Herskowitz I, O'Shea EK (2002) Yeast go the whole HOG for the hyperosmotic response. Trends Genet 18:405–412

    Article  CAS  PubMed  Google Scholar 

  • Ozier-Kalogeropoulos O, Malpertuy A, Boyer J, Tekaia F, Dujon B (1998) Random exploration of the Kluyveromyces lactis genome and comparison with that of Saccharomyces cerevisiae. Nucleic Acids Res 26:5511–5524

    CAS  PubMed  Google Scholar 

  • Pan X, Heitman J (1999) Cyclic AMP-dependent protein kinase regulates pseudohyphal differentiation in Saccharomyces cerevisiae. Mol Cell Biol 19:4874–4887

    Google Scholar 

  • Pan X, Heitman J (2002) Protein kinase A operates a molecular switch that governs yeast pseudohyphal differentiation. Mol Cell Biol 22:3981–3993

    Article  CAS  PubMed  Google Scholar 

  • Pan X, Harashima T, Heitman J (2000) Signal transduction cascades regulating pseudohyphal differentiation of Saccharomyces cerevisiae. Curr Opin Microbiol 3:567–572

    CAS  PubMed  Google Scholar 

  • Peter M, Neiman AM, Park HO, Lohuizen M van, Herskowitz I (1996) Functional analysis of the interaction between the small GTP binding protein Cdc42 and the Ste20 protein kinase in yeast. EMBO J 15:7046–7059

    CAS  PubMed  Google Scholar 

  • Ponting CP (1995) SAM: a novel motif in yeast sterile and Drosophila polyhomeotic proteins. Protein Sci 4:1928–1930

    CAS  PubMed  Google Scholar 

  • Ponting CP, Benjamin DR (1996) A novel family of Ras-binding domains. Trends Biochem Sci 21:422–425

    CAS  PubMed  Google Scholar 

  • Posas F, Saito H (1997) Osmotic activation of the HOG MAPK pathway via Ste11p MAPKKK: scaffold role of Pbs2p MAPKK. Science 276:1702–1705

    CAS  PubMed  Google Scholar 

  • Posas F, Saito H (1998) Activation of the yeast SSK2 MAP kinase kinase kinase by the SSK1 two-component response regulator. EMBO J 17:1385–1394

    Article  CAS  PubMed  Google Scholar 

  • Posas F, Witten EA, Saito H (1998) Requirement of STE50 for osmostress-induced activation of the STE11 mitogen-activated protein kinase kinase kinase in the high-osmolarity glycerol response pathway. Mol Cell Biol 18:5788–5796

    CAS  PubMed  Google Scholar 

  • Printen JA, Sprague GF Jr (1994) Protein–protein interactions in the yeast pheromone response pathway: Ste5p interacts with all members of the MAP kinase cascade. Genetics 138:609–619

    CAS  PubMed  Google Scholar 

  • Pryciak PM (2001) MAP kinases bite back. Dev Cell 1:449–451

    CAS  PubMed  Google Scholar 

  • Pryciak PM, Huntress FA (1998) Membrane recruitment of the kinase cascade scaffold protein Ste5 by the Gbetagamma complex underlies activation of the yeast pheromone response pathway. Genes Dev 12:2684–2697

    CAS  PubMed  Google Scholar 

  • Racki WJ, Becam AM, Nasr F, Herbert CJ (2000) Cbk1p, a protein similar to the human myotonic dystrophy kinase, is essential for normal morphogenesis in Saccharomyces cerevisiae. EMBO J 19:4524–4532

    CAS  PubMed  Google Scholar 

  • Raitt DC, Posas F, Saito H (2000) Yeast Cdc42 GTPase and Ste20 PAK-like kinase regulate Sho1-dependent activation of the Hog1 MAPK pathway. EMBO J 19:4623–4631

    Article  CAS  PubMed  Google Scholar 

  • Ramachander R, Kim CA, Phillips ML, Mackereth CD, Thanos CD, McIntosh LP, Bowie JU (2002) Oligomerization-dependent association of the SAM domains from Schizosaccharomyces pombe Byr2 and Ste4. J Biol Chem 277:39585–39593

    Article  CAS  PubMed  Google Scholar 

  • Ramezani Rad M, Lützenkirchen K, Xu G, Kleinhans U, Hollenberg CP (1991) The complete sequence of a 11,953 bp fragment from C1G on chromosome III encompasses four open reading frames. Yeast 7:533–538

    PubMed  Google Scholar 

  • Ramezani Rad M, Xu G, Hollenberg CP (1992) STE50, a novel gene required for activation of conjugation at an early step in mating in Saccharomyces cerevisiae. Mol Gen Genet 236:145–154

    PubMed  Google Scholar 

  • Ramezani Rad M, Jansen G, Buhring F, Hollenberg CP (1998) Ste50p is involved in regulating filamentous growth in the yeast Saccharomyces cerevisiae and associates with Ste11p. Mol Gen Genet 259:29–38

    Article  CAS  PubMed  Google Scholar 

  • Reiser V, Salah SM, Ammerer G (2000) Polarized localization of yeast Pbs2 depends on osmostress, the membrane protein Sho1 and Cdc42. Nat Cell Biol 2:620–627

    Article  CAS  PubMed  Google Scholar 

  • Robertson LS, Fink GR (1998) The three yeast A kinases have specific signaling functions in pseudohyphal growth. Proc Natl Acad Sci USA 95:13783–13787

    CAS  PubMed  Google Scholar 

  • Rupp S, Summers E, Lo HJ, Madhani H, Fink G (1999) MAP kinase and cAMP filamentation signaling pathways converge on the unusually large promoter of the yeast FLO11 gene. EMBO J 18:1257–1269

    CAS  PubMed  Google Scholar 

  • Schultz J, Ponting CP, Hofmann K, Bork P (1997) SAM as a protein interaction domain involved in developmental regulation. Protein Sci 6:249–253

    CAS  PubMed  Google Scholar 

  • Simon MN, De Virgilio C, Souza B, Pringle JR, Abo A, Reed SI (1995) Role for the Rho-family GTPase Cdc42 in yeast mating-pheromone signal pathway. Nature 376:702–705

    CAS  PubMed  Google Scholar 

  • Stevenson BJ, Rhodes N, Errede B, Sprague GF Jr (1992) Constitutive mutants of the protein kinase STE11 activate the yeast pheromone response pathway in the absence of the G protein. Genes Dev 6:1293–1304

    CAS  PubMed  Google Scholar 

  • Thompson JD, Higgins DG, Gibson TJ (1994) CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 22:4673–4680

    PubMed  Google Scholar 

  • Tu H, Barr M, Dong DL, Wigler M (1997) Multiple regulatory domains on the Byr2 protein kinase. Mol Cell Biol 17:5876–5887

    CAS  PubMed  Google Scholar 

  • Vaughan-Martini A, Martini A (1998) Saccharomyces Meyen ex Reess. In: Kurtzman CP, Fell JW (eds) The yeasts, a taxonomic study. Elsevier, Amsterdam, pp 358–371

  • Vetter IR, Linnemann T, Wohlgemuth S, Geyer M, Kalbitzer HR, Herrmann C, Wittinghofer A (1999) Structural and biochemical analysis of Ras-effector signaling via RalGDS. FEBS Lett 451:175–180

    CAS  PubMed  Google Scholar 

  • Whiteway MS, Wu C, Leeuw T, Clark K, Fourest-Lieuvin A, Thomas DY, Leberer E (1995) Association of the yeast pheromone response G protein beta gamma subunits with the MAP kinase scaffold Ste5p. Science 269:1572–1575

    CAS  PubMed  Google Scholar 

  • Wu C, Whiteway M, Thomas DY, Leberer E (1995) Molecular characterization of Ste20p, a potential mitogen-activated protein or extracellular signal-regulated kinase kinase (MEK) kinase kinase from Saccharomyces cerevisiae. J Biol Chem 270:15984–15992

    Article  CAS  PubMed  Google Scholar 

  • Wu C, Leeuw T, Leberer E, Thomas DY, Whiteway M (1998) Cell cycle- and Cln2p-Cdc28p-dependent phosphorylation of the yeast Ste20p protein kinase. J Biol Chem 273:28107–28115

    Article  CAS  PubMed  Google Scholar 

  • Wu C, Leberer E, Thomas DY, Whiteway M (1999) Functional characterisation of the interaction of Ste50p with Ste11p MAPKKK in Saccharomyces cerevisiae. Mol Cell Biol 10:2425–2440

    CAS  Google Scholar 

  • Wurgler-Murphy SM, Maeda T, Witten EA, Saito H (1997) Regulation of the Saccharomyces cerevisiae HOG1 mitogen-activated protein kinase by the PTP2 and PTP3 protein tyrosine phosphatases. Mol Cell Biol 17:1289–1297

    CAS  PubMed  Google Scholar 

  • Wuytswinkel O van, Reiser V, Siderius M, Kelders MC, Ammerer G, Ruis H, Mager WH (2000) Response of Saccharomyces cerevisiae to severe osmotic stress: evidence for a novel activation mechanism of the HOG MAP kinase pathway. Mol Microbiol 37:382–397

    Article  PubMed  Google Scholar 

  • Xu G, Jansen G, Thomas DY, Hollenberg CP, Ramezani Rad M (1996) Ste50p sustains mating pheromone-induced signal transduction in the yeast Saccharomyces cerevisiae. Mol Microbiol 20:773–783

    CAS  PubMed  Google Scholar 

  • Zhao ZS, Leung T, Manser E, Lim L (1995) Pheromone signalling in Saccharomyces cerevisiae requires the small GTP-binding protein Cdc42p and its activator CDC24. Mol Cell Biol 15:5246–5257

    CAS  PubMed  Google Scholar 

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Acknowledgements

I want to thank Hannelore Gurk, Ulrich Gueldener and members of my group for all their help and I am grateful to Paul Hardy for reading the manuscript and for helpful discussions. I thank the two anonymous referees of an earlier version of this review for very specific comments and suggestions. This study is in part supported by a grant from the Deutsche Forschungsgemeinschaft.

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  1. Institut für Mikrobiologie, Heinrich-Heine-Universität Düsseldorf, Universitätsstrasse 1, Geb. 26.12, 40225, Düsseldorf, Germany

    Massoud Ramezani-Rad

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Correspondence to Massoud Ramezani-Rad.

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Ramezani-Rad, M. The role of adaptor protein Ste50-dependent regulation of the MAPKKK Ste11 in multiple signalling pathways of yeast. Curr Genet 43, 161–170 (2003). https://doi.org/10.1007/s00294-003-0383-6

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