Abstract
BackgroundThe S. cerevisiae MAPKKK Ste11p, a homologue of mammalian MEKK1, regulates three MAPK cascades for mating, invasive growth and osmotic stress and provides functions that are additive with the cell wall integrity pathway. Cell wall integrity requires the FKS2 gene that encodes a stress-induced alternative subunit of beta-1, 3 glucan synthase that is the target of echinocandin 1,3- beta glucan synthase inhibitors. The major signal transduction pathways that activate transcription of the FKS2 gene include the cell wall integrity and calcineurin pathways, and the Ste11p pathway.ResultsHere it is shown that catalytically active Ste11p regulates FKS2-lacZ reporter genes through Ste12, calcineurin/Crz1p- and PKC pathways and the high osmolarity pathway. Ste11p stimulated the cell wall integrity MAPK Mpk1p (Erk5 homologue) and FKS2 independently of the mating pathway. Ste11p regulated FKS2 through all known and putative substrates: Pbs2p MAPKK, Ste7 MAPKK, Cmk2p calmodulin dependent kinase and Ptk2p kinase. Ste11p increased the expression level of Cmk2p through transcription-dependent and -independent mechanisms.ConclusionsThe data suggest Ste11p regulates the FKS2 gene through all its known and putative downstream kinase substrates (Pbs2p, Ste7p, Cmk2p, and Ptk2p) and separately through Mpk1p MAPK. The patterns of control by Ste11p targets revealed novel functional linkages, cross-regulation, redundancy and compensation.
Highlights
The S. cerevisiae mitogen activated protein kinase kinase kinase (MAPKKK) Ste11p, a homologue of mammalian MEKK1, regulates three MAPK cascades for mating, invasive growth and osmotic stress and provides functions that are additive with the cell wall integrity pathway
Ste11p is required for basal Slt2p/Mpk1p activation Prior work indicated that Ste11p is functionally redundant with the Bck1p MAPKKK for cell integrity during vegetative growth and could basally activate the cell wall integrity target FKS2 gene using a well established FKS2 (-928 to +6)-lacZ reporter gene [2]
To test the possibility that Ste11p regulates cell integrity through activation of the PKC pathway during vegetative growth, we assessed the basal level of active Mpk1p in three yeast strain backgrounds, S288c, W303a and ∑1278b by probing whole cell extracts with a mammalian phosphop42p44 antibody that cross-reacts with S. cerevisiae Slt2p/Mpk1p [25]
Summary
The S. cerevisiae MAPKKK Ste11p, a homologue of mammalian MEKK1, regulates three MAPK cascades for mating, invasive growth and osmotic stress and provides functions that are additive with the cell wall integrity pathway. Ste11p encodes a mitogen activated protein kinase kinase kinase (MAPKKK) that activates conserved MAPK pathways controlling mating, high osmolarity glycerol (HOG), invasive growth and the FKS2 gene in the cell wall integrity pathway [1,2,3]. Prior work suggests that Ste11p MAPKKK signals through MAPK Kss1p to positively regulate cell wall integrity [2] This analysis revealed that Ste11p has functional redundancy with the Bck1p MAPKKK in the PKC pathway and can activate the expression of the FKS2 gene [2]. FKS2 is expressed at low levels and is upregulated under conditions of stress, higher temperature, when FKS1 is mutated, reduced carbon source [1], and when glycosylation is disrupted [2]
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