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• W2008034301 abstract "A paper in a recent issue of Current Biology from Kozubowski et al. [1Kozubowski L. Saito K. Johnson J.M. Howell A.S. Zyla T.R. Lew D.J. Symmetry-breaking polarization driven by a Cdc42p GEF-PAK complex.Curr. Biol. 2008; 18: 1719-1726Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar] concluded that spontaneous symmetry breaking in yeast can be explained by the formation of a Bem1-mediated complex between Cdc24 (the guanine nucleotide exchange factor (GEF) for Cdc42) and the p21-activated kinase (PAK) Cla4. A previous finding, on which this paper was based, is that a rsr1Δ bem1Δ double mutant is inviable. Because Rsr1 is required for polarization in response to the position of the previous bud scar [2Chant J. Herskowitz I. Genetic control of bud site selection in yeast by a set of gene products that constitute a morphogenetic pathway.Cell. 1991; 65: 1203-1212Abstract Full Text PDF PubMed Scopus (302) Google Scholar], a process known as bud site selection, it was assumed that this synthetic lethality reflects an essential role for Bem1 in spontaneous cell polarization in the absence of the bud scar cue (referred to as symmetry-breaking polarization by Kozubowski et al. [1Kozubowski L. Saito K. Johnson J.M. Howell A.S. Zyla T.R. Lew D.J. Symmetry-breaking polarization driven by a Cdc42p GEF-PAK complex.Curr. Biol. 2008; 18: 1719-1726Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar]). On the basis of this assumption, a central aim of the present study was to test whether Bem1's role was simply to tether Cdc24 to Cla4, which then phosphorylates Cdc24 [3Gulli M.P. Jaquenoud M. Shimada Y. Niederhauser G. Wiget P. Peter M. Phosphorylation of the Cdc42 exchange factor Cdc24 by the PAK-like kinase Cla4 may regulate polarized growth in yeast.Mol. Cell. 2000; 6: 1155-1167Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar, 4Bose I. Irazoqui J.E. Moskow J.J. Bardes E.S. Zyla T.R. Lew D.J. Assembly of scaffold-mediated complexes containing Cdc42p, the exchange factor Cdc24p, and the effector Cla4p required for cell cycle-regulated phosphorylation of Cdc24p.J. Biol. Chem. 2001; 276: 7176-7186Crossref PubMed Scopus (153) Google Scholar]. To this end, the authors generated a construct that artificially linked Cdc24 and Cla4 and found that this construct could rescue the lethality of the rsr1Δ bem1Δ double mutant. In the light of this result and the assumption that phosphorylation by Cla4 positively regulates Cdc24, they proposed a model in which formation of a complex between Cdc24 and Cla4 creates a feedback loop for Cdc42 activation and is sufficient to drive symmetry breaking in yeast. A paper in a recent issue of Current Biology from Kozubowski et al. [1Kozubowski L. Saito K. Johnson J.M. Howell A.S. Zyla T.R. Lew D.J. Symmetry-breaking polarization driven by a Cdc42p GEF-PAK complex.Curr. Biol. 2008; 18: 1719-1726Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar] concluded that spontaneous symmetry breaking in yeast can be explained by the formation of a Bem1-mediated complex between Cdc24 (the guanine nucleotide exchange factor (GEF) for Cdc42) and the p21-activated kinase (PAK) Cla4. A previous finding, on which this paper was based, is that a rsr1Δ bem1Δ double mutant is inviable. Because Rsr1 is required for polarization in response to the position of the previous bud scar [2Chant J. Herskowitz I. Genetic control of bud site selection in yeast by a set of gene products that constitute a morphogenetic pathway.Cell. 1991; 65: 1203-1212Abstract Full Text PDF PubMed Scopus (302) Google Scholar], a process known as bud site selection, it was assumed that this synthetic lethality reflects an essential role for Bem1 in spontaneous cell polarization in the absence of the bud scar cue (referred to as symmetry-breaking polarization by Kozubowski et al. [1Kozubowski L. Saito K. Johnson J.M. Howell A.S. Zyla T.R. Lew D.J. Symmetry-breaking polarization driven by a Cdc42p GEF-PAK complex.Curr. Biol. 2008; 18: 1719-1726Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar]). On the basis of this assumption, a central aim of the present study was to test whether Bem1's role was simply to tether Cdc24 to Cla4, which then phosphorylates Cdc24 [3Gulli M.P. Jaquenoud M. Shimada Y. Niederhauser G. Wiget P. Peter M. Phosphorylation of the Cdc42 exchange factor Cdc24 by the PAK-like kinase Cla4 may regulate polarized growth in yeast.Mol. Cell. 2000; 6: 1155-1167Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar, 4Bose I. Irazoqui J.E. Moskow J.J. Bardes E.S. Zyla T.R. Lew D.J. Assembly of scaffold-mediated complexes containing Cdc42p, the exchange factor Cdc24p, and the effector Cla4p required for cell cycle-regulated phosphorylation of Cdc24p.J. Biol. Chem. 2001; 276: 7176-7186Crossref PubMed Scopus (153) Google Scholar]. To this end, the authors generated a construct that artificially linked Cdc24 and Cla4 and found that this construct could rescue the lethality of the rsr1Δ bem1Δ double mutant. In the light of this result and the assumption that phosphorylation by Cla4 positively regulates Cdc24, they proposed a model in which formation of a complex between Cdc24 and Cla4 creates a feedback loop for Cdc42 activation and is sufficient to drive symmetry breaking in yeast. Although the result that the Cdc24–Cla4 chimera rescued the rsr1Δ bem1Δ double mutant is interesting, there is a significant alternative interpretation that would not warrant any conclusions regarding the mechanism of symmetry breaking. A key aspect of the authors' model that has remained a long-standing mystery is the mechanism of activation and membrane localization of the GEF Cdc24. While the authors are in favor of the model that phosphorylation of Cdc24 by Cla4 would positively regulate these processes, results from two previous studies argued against this possibility [3Gulli M.P. Jaquenoud M. Shimada Y. Niederhauser G. Wiget P. Peter M. Phosphorylation of the Cdc42 exchange factor Cdc24 by the PAK-like kinase Cla4 may regulate polarized growth in yeast.Mol. Cell. 2000; 6: 1155-1167Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar, 5Weiss E.L. Bishop A.C. Shokat K.M. Drubin D.G. Chemical genetic analysis of the budding-yeast p21-activated kinase Cla4p.Nat. Cell Biol. 2000; 2: 677-685Crossref PubMed Scopus (109) Google Scholar]. More importantly, Kozubowski et al. [1Kozubowski L. Saito K. Johnson J.M. Howell A.S. Zyla T.R. Lew D.J. Symmetry-breaking polarization driven by a Cdc42p GEF-PAK complex.Curr. Biol. 2008; 18: 1719-1726Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar] neglected a previous study that suggested that Rsr1 and Bem1 both contribute to Cdc24 activation by directly binding the GEF, relieving an auto-inhibited conformation and allowing membrane association [6Shimada Y. Wiget P. Gulli M.P. Bi E. Peter M. The nucleotide exchange factor Cdc24p may be regulated by auto-inhibition.EMBO J. 2004; 23: 1051-1062Crossref PubMed Scopus (66) Google Scholar]. The physiological function of Rsr1 in cell polarization is known to require its GTPase cycle and the GTP-bound form of Rsr1 binds preferentially to Cdc24 [7Park H.O. Chant J. Herskowitz I. BUD2 encodes a GTPase activating protein for Bud1/Rsr1 necessary for proper bud-site selection in yeast.Nature. 1993; 365: 269-274Crossref PubMed Scopus (136) Google Scholar, 8Zheng Y. Bender A. Cerione R.A. Interactions among proteins involved in bud-site selection and bud site assembly in Saccharomyces cerevisiae.J. Biol. Chem. 1995; 270: 626-630Crossref PubMed Scopus (147) Google Scholar, 9Park H.O. Bi E. Pringle J.R. Herskowitz I. Two active states of the Ras-related Bud1/Rsr1 protein bind to different effectors to determine yeast cell polarity.Proc. Natl. Acad. Sci. USA. 1997; 94: 4463-4468Crossref PubMed Scopus (146) Google Scholar]. This could potentially allow Rsr1 to activate Cdc24 in a catalytic manner through the GTPase cycle, enabling efficient binding and release of Cdc24, analogous to the way in which the GEF activates Cdc42. The GTPase cycle also enables Rsr1 to interact dynamically with Bem1 [9Park H.O. Bi E. Pringle J.R. Herskowitz I. Two active states of the Ras-related Bud1/Rsr1 protein bind to different effectors to determine yeast cell polarity.Proc. Natl. Acad. Sci. USA. 1997; 94: 4463-4468Crossref PubMed Scopus (146) Google Scholar]. Regardless of the detailed biochemical mechanism, because Cdc24 is essential irrespective of the mode of polarization, the synthetic lethality of rsr1Δ bem1Δ could be most simply explained by a lack of GEF activation rather than a specific defect in symmetry breaking. Rescuing this lethality by the chimera would thus suggest that artificially linking Cla4 to Cdc24 allows the GEF to be activated independently of Bud1 or Bem1. This becomes even more likely when considering that the proposed autoinhibitory regions of Cdc24 are removed in the chimeras. Without separating GEF activation from the actual polarization event, the rescue result does not provide any conclusive evidence that formation of the Cdc24–Cla4 complex is the key step in symmetry breaking. Previous studies also showed that Bem1 does not represent the only mechanism for polarization in random orientations (relative to the bud scar); there is a mechanism of symmetry breaking that involves a feedback loop between actin-based transport and Cdc42-controlled actin cable formation [10Wedlich-Soldner R. Altschuler S. Wu L. Li R. Spontaneous cell polarization through actomyosin-based delivery of the Cdc42 GTPase.Science. 2003; 299: 1231-1235Crossref PubMed Scopus (315) Google Scholar, 11Wedlich-Soldner R. Wai S.C. Schmidt T. Li R. Robust cell polarity is a dynamic state established by coupling transport and GTPase signaling.J. Cell Biol. 2004; 166: 889-900Crossref PubMed Scopus (167) Google Scholar]. This pathway of spontaneous polarization was tested using the actin inhibitor latrunculin A (LatA) as well as temperature-sensitive mutations specifically disrupting actin-cable-mediated transport or fusion of secretory vesicles. Disruption of either actin or Bem1 alone did not prevent polarization, but cells were completely unable to polarize when both pathways were inhibited [11Wedlich-Soldner R. Wai S.C. Schmidt T. Li R. Robust cell polarity is a dynamic state established by coupling transport and GTPase signaling.J. Cell Biol. 2004; 166: 889-900Crossref PubMed Scopus (167) Google Scholar]. Given this redundancy, experiments must be carried out with the other pathway disabled in order to interpret the effects of mutations on a specific polarization pathway. However, Kozubowski et al. [1Kozubowski L. Saito K. Johnson J.M. Howell A.S. Zyla T.R. Lew D.J. Symmetry-breaking polarization driven by a Cdc42p GEF-PAK complex.Curr. Biol. 2008; 18: 1719-1726Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar] did not test whether the rsr1Δ bem1Δ strain bearing the Cdc24–Cla4 chimera or any other mutant constructs could polarize in the presence of LatA or mutations that disrupt vesicular transport. Without such experiments, there is no specific evidence supporting a model for symmetry breaking that is based solely on the formation of the Bem1–GEF–PAK complex and excludes the contribution of actin or transport. For example, an equally plausible explanation of the authors' results is that the rsr1Δ bem1Δ cells bearing the Cdc24–Cla4 chimera were polarizing through the actin-based mechanism in Bem1's absence, and Cdc24–Cla4 chimeras simply provide a high level of active GEF for the generation of Cdc42–GTP. No doubt, how cells can break symmetry independently of the cytoskeleton is an interesting problem; however, it is questionable whether the minimalist model proposed by the authors would be capable of symmetry breaking even with the possible presence of a feedback loop (note that it remains unknown whether phosphorylation by Cla4 indeed activates the GEF or promotes its membrane association, which would be an important part of the feedback loop). Even though a number of theoretical studies suggest that positive feedback loops can potentially drive symmetry breaking [10Wedlich-Soldner R. Altschuler S. Wu L. Li R. Spontaneous cell polarization through actomyosin-based delivery of the Cdc42 GTPase.Science. 2003; 299: 1231-1235Crossref PubMed Scopus (315) Google Scholar, 12Meinhardt H. Gierer A. Pattern formation by local self-activation and lateral inhibition.BioEssays. 2000; 22: 753-760Crossref PubMed Scopus (440) Google Scholar, 13Altschuler S.J. Angenent S.B. Wang Y. Wu L.F. On the spontaneous emergence of cell polarity.Nature. 2008; 454: 886-889Crossref PubMed Scopus (165) Google Scholar], these models all require important additional assumptions and could only produce unique polarity within specific parameter spaces. Whereas the reported interactions could well contribute to yeast polarization, the key mechanism that can explain spontaneous symmetry breaking without participation of the cytoskeleton remains to be identified." @default.
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• W2008034301 title "Bem1 complexes and the complexity of yeast cell polarization" @default.
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