title: Response regulator-mediated MAPKKK heteromer promotes stress signaling to the Spc1 MAPK in fission yeast.
abstract: The Spc1 mitogen-activated protein kinase (MAPK) cascade in fission yeast is activated by two MAPK kinase kinase (MAPKKK) paralogues, Wis4 and Win1, in response to multiple forms of environmental stress. Previous studies identified Mcs4, a "response regulator" protein that associates with the MAPKKKs and receives peroxide stress signals by phosphorelay from the Mak2/Mak3 sensor histidine kinases. Here we show that Mcs4 has an unexpected, phosphorelay-independent function in promoting heteromer association between the Wis4 and Win1 MAPKKKs. Only one of the MAPKKKs in the heteromer complex needs to be catalytically active, but disturbing the integrity of the complex by mutations to Mcs4, Wis4, or Win1 results in reduced MAPKKK-MAPKK interaction and, consequently, compromised MAPK activation. The physical interaction among Mcs4, Wis4, and Win1 is constitutive and not responsive to stress stimuli. Therefore the Mcs4-MAPKKK heteromer complex might serve as a stable platform/scaffold for signaling proteins that convey input and output of different stress signals. The Wis4-Win1 complex discovered in fission yeast demonstrates that heteromer-mediated mechanisms are not limited to mammalian MAPKKKs.
authors: Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Nara, Japan.
authors: Susumu
authors: S
authors: Morigasaki
authors: Aminah
authors: A
authors: Ikner
authors: Hisashi
authors: H
authors: Tatebe
authors: Kazuhiro
authors: K
authors: Shiozaki
mesh_terms: D000595:Amino Acid Sequence; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D015151:Immunoblotting; D020930:MAP Kinase Kinase Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D009997:Osmotic Pressure; D010766:Phosphorylation; D011485:Protein Binding; D055503:Protein Multimerization; D012568:Schizosaccharomyces / Q000235:genetics / Q000378:metabolism*; D029702:Schizosaccharomyces pombe Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013312:Stress, Physiological; D020798:Two-Hybrid System Techniques
chemical_list: D018797:Cell Cycle Proteins; C105788:Mcs4 protein, S pombe; D029702:Schizosaccharomyces pombe Proteins; D020928:Mitogen-Activated Protein Kinases; C524689:Spc1 protein, S pombe; D020930:MAP Kinase Kinase Kinases; C109170:win1 protein, S pombe; C109169:wis4 protein, S pombe; D020929:Mitogen-Activated Protein Kinase Kinases; C072068:wis1 protein, S pombe
references: FEBS Lett. 2006 May 1;580(10):2409-13
references: 16603158
references: J Biol Chem. 1990 Jul 5;265(19):10857-64
references: 2358444
references: Science. 1995 Jul 28;269(5223):554-8
references: 7624781
references: Nature. 1996 Aug 29;382(6594):822-6
references: 8752278
references: Oncogene. 2007 May 14;26(22):3159-71
references: 17496913
references: Nature. 2005 May 26;435(7041):507-12
references: 15917811
references: Genes Dev. 1995 Sep 1;9(17):2117-30
references: 7657164
references: Genes Dev. 1999 Jul 1;13(13):1653-63
references: 10398679
references: Mol Cell. 2008 Apr 11;30(1):108-13
references: 18406331
references: Science. 1993 Mar 19;259(5102):1760-3
references: 7681220
references: Genes Dev. 1997 Apr 15;11(8):1008-22
references: 9136929
references: Oncogene. 2007 May 14;26(22):3185-202
references: 17496915
references: Cell. 1996 Sep 20;86(6):865-75
references: 8808622
references: Yeast. 1998 Jul;14(10):943-51
references: 9717240
references: Mol Cell Biol. 2007 Apr;27(7):2765-76
references: 17242196
references: Mol Biol Cell. 2002 Mar;13(3):805-16
references: 11907263
references: Mol Biol Cell. 2001 Feb;12(2):407-19
references: 11179424
references: Cell. 1998 Nov 13;95(4):521-30
references: 9827804
references: EMBO J. 1997 Oct 15;16(20):6162-70
references: 9321395
references: Mol Cell Biol. 2003 Aug;23(15):5132-42
references: 12861001
references: Genes Dev. 1996 Sep 15;10(18):2276-88
references: 8824587
references: Mol Biol Cell. 1998 Jun;9(6):1339-49
references: 9614178
references: Curr Biol. 2005 Jun 7;15(11):1006-15
references: 15936270
references: Genes Dev. 1996 Sep 15;10(18):2289-301
references: 8824588
references: Mol Biol Cell. 2003 Jan;14(1):214-29
references: 12529438
references: Mol Biol Cell. 1998 Aug;9(8):2325-35
references: 9693384
references: Mol Cell. 2005 Dec 22;20(6):963-9
references: 16364920
references: Mol Biol Cell. 1997 Mar;8(3):409-19
references: 9188094
references: J Biol Chem. 2007 Mar 9;282(10):7522-31
references: 17210579
references: Science. 2010 May 21;328(5981):1043-6
references: 20489023
references: Nat Cell Biol. 2008 Nov;10(11):1324-32
references: 18836437
references: Mol Cell Biol. 1996 Jun;16(6):2870-7
references: 8649397
references: Methods Enzymol. 1997;283:506-20
references: 9251044
references: Nat Cell Biol. 2007 Nov;9(11):1263-72
references: 17952063
references: Cancer Res. 2001 May 1;61(9):3595-8
references: 11325826
references: Science. 1997 Jun 13;276(5319):1702-5
references: 9180081
references: Mol Biol Cell. 2000 Apr;11(4):1169-81
references: 10749922
references: EMBO J. 1998 Mar 2;17(5):1385-94
references: 9482735
references: Nature. 1994 May 19;369(6477):242-5
references: 8183345
references: Mol Cell Biol. 2002 Jul;22(13):4544-55
references: 12052864
references: Annu Rev Cell Dev Biol. 2003;19:91-118
references: 14570565
references: Physiol Rev. 2012 Apr;92(2):689-737
references: 22535895
references: Nucleic Acids Res. 2010 Jul;38(Web Server issue):W695-9
references: 20439314
references: Curr Opin Microbiol. 2010 Apr;13(2):160-7
references: 20080056
references: Mol Cell Biol. 2008 Sep;28(17):5172-83
references: 18573873
references: Methods Enzymol. 2010;471:279-89
references: 20946853
references: Mol Cell Biol. 2005 May;25(10):3945-55
references: 15870269
references: Nature. 1995 Dec 14;378(6558):739-43
references: 7501024