Abstract: ABSTRACT: BACKGROUND: 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. 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. RESULTS: Here 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. CONCLUSIONS: The 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.