Disease relevance of STE11

• Despite the fact that YFW1, YFW12, and YFW16/STE11 each confer substantial MMS resistance upon E. coli alkB cells, S. cerevisiae null mutants for each gene were not MMS sensitive [1].

High impact information on STE11

• Set2 functioned upstream of Rpd3S and the Eaf3 methyl-histone binding chromodomain was important for recruitment of Rpd3S and for deacetylation within the STE11 ORF [2].
• Ste5 copurifies with Ste11, Fus3, and a hypophosphorylated form of Ste7, and all four proteins cosediment in a glycerol gradient as if in a large complex [3].
• FUS3/KSS1 phosphorylation depends on two additional kinases, STE11 and STE7 (refs 2, 5, 6) [4].
• Osmotic activation of the HOG MAPK pathway via Ste11p MAPKKK: scaffold role of Pbs2p MAPKK [5].
• Adaptor protein Ste50p links the Ste11p MEKK to the HOG pathway through plasma membrane association [6].

Biological context of STE11

• Order of action of components in the yeast pheromone response pathway revealed with a dominant allele of the STE11 kinase and the multiple phosphorylation of the STE7 kinase [7].
• The signal transduction pathway that mediates the response of haploid yeast cells to peptide mating pheromones involves several components including the protein kinases STE7 and STE11 [7].
• We also have genetically mapped the STE11 gene to chromosome XII, 40 centimorgans from ura4 [8].
• Ste20, which phosphorylates Ste11 to initiate signaling, is activated by binding to Cdc42 GTPase (membrane anchored via its C-terminal geranylgeranylation) [9].
• Among the components necessary for signal transduction are the STE7 and STE11 kinases and either one of the redundant FUS3 and KSS1 kinases [10].

Anatomical context of STE11

• The RA domain of Ste50 adaptor protein is required for delivery of Ste11 to the plasma membrane in the filamentous growth signaling pathway of the yeast Saccharomyces cerevisiae [9].
• Injection of recombinant STE11 protein (a yeast MAPKK kinase) also induced initiation of oocyte maturation [11].
• Injection of an N-terminal truncated STE11 protein (delta N-STE11), a constitutively active form of STE11 which is a yeast MAPKK kinase, induced neurite outgrowth in PC12 cells [12].
• Once Ste11 is activated, signaling through the mating pathway remains minimal but is substantially amplified when Ste5 is recruited to the membrane either by the Gbetagamma dimer or by direct membrane targeting, even to internal membranes [13].
• Functional analysis of a C. glabrata ste11 null mutant demonstrates that Ste11 is required for adaptation to hypertonic stress but is largely dispensable for maintenance of cell wall integrity [14].

Associations of STE11 with chemical compounds

• Requirement of STE50 for osmostress-induced activation of the STE11 mitogen-activated protein kinase kinase kinase in the high-osmolarity glycerol response pathway [15].
• These results suggest that the Arabidopsis cDNA encodes a putative serine/threonine kinase that can function in the mating response pathway upstream of FUS3/KSS1 in S. cerevisiae, at the level of STE11 gene [16].
• Furthermore, in the presence of cycloheximide, the STE11-induced activation of MPF as well as the induction and accumulation of Mos was blocked, and the activation of MAPK was greatly reduced [11].
• MEK, in turn, may be activated following its phosphorylation on serine by either of the kinases encoded by proto-oncogenes raf1 or mos, as well as by p78mekk, which is related to the yeast STE11 and byr2 gene products [17].
• Mutational analysis suggests that the leucine-rich domain limits the accessibility of the RING-H2 domain and inhibits export and recruitment in addition to promoting Ste11 association and activation [18].

Physical interactions of STE11

• In a two-hybrid assay Ste50p interacts weakly with the G protein and strongly with the MAPKKK Ste11p [19].
• Measurement of relative binding affinities showed that the STE11 protein tightly interacts with the STE5 protein for its stabilization [20].
• Bud6p interacts with Ste11p [21].
• We have found a region in the C terminus of Sho1 that binds Ste11 independently of Pbs2 and is required for crosstalk [22].
• CDC37 overexpression also restored stable Hsp90 binding to the Ste11 protein kinase domain in the sti1Delta mutant strain [23].

Enzymatic interactions of STE11

• RESULTS: Ste20p phosphorylated Ste11p on Ser302 and/or Ser306 and Thr307 in yeast, residues that are conserved in MEKKs of other organisms [24].

Regulatory relationships of STE11

• Increased Cln2 levels repress the ability of hyperactive STE11 alleles to induce the pathway [25].
• Overexpression of STE11 also suppresses the mating defects of ste50 mutants [26].
• Nonetheless, previous work has shown that Ste11 can be activated even when Pbs2 is deleted, resulting in inappropriate crosstalk to the mating pathway [22].
• Ste20 activates Ste11 by derepressing an autoinhibitory domain [27].
• Byr1 and Ste7 are in turn regulated by the protein kinases Byr2 and Ste11 [28].

Other interactions of STE11

• The second mechanism of HOG1 MAP kinase activation is independent of the two-component osmosensor and involves the SHO1 transmembrane protein and the STE11 MAPKKK [15].
• We have found that L73A and L75A abrogate the Ste50p interaction with Ste11p, and we compare these data with the known interaction sites defined for other SAM domain interactions [29].
• Therefore our results suggest that Cln2-dependent repression of the mating pathway occurs at the level of Ste11 [25].
• Mutations that affect association with Ste7 or with Ste11 delineate discrete regions of Ste5 that are critical for each interaction [30].
• Epistasis tests between dfg mutant alleles and dominant activated alleles of the RAS2 and STE11 genes, RAS2Val19 and STE11-4, respectively, identify putative targets for the filamentation signaling pathway [31].

Analytical, diagnostic and therapeutic context of STE11

• We report here the molecular cloning of STE7 and STE11 genes and show that expression of these genes is not regulated transcriptionally by the MAT locus [8].
• Immunodetection and Northern blot analyses showed that the low level of the STE5 protein in the ste11 delta mutant is not due to the level of gene expression but to that of protein stability [20].
• To obtain a genomewide view of Ste11p target genes, their cell-type specificity, and their dependence on pheromone, we used DNA microarrays along with different genetic and environmental manipulations of fission yeast cells [32].

References