Disease relevance of STE4

• On the other hand, sterility resulting from deletion of STE4 was not suppressed by the mot2 deletion [1].

High impact information on STE4

• Sequencing of the cloned genes revealed that the STE4 polypeptide shows extensive homology to the beta subunits of mammalian G proteins, while the STE18 polypeptide shows weak similarity to the gamma subunit of transducin [2].
• Analysis of double mutants suggests that the STE4 gene product functions after the SCG1 product but before the STE5 product [3].
• The STE4 and STE18 genes are required for haploid yeast cell mating [2].
• Ste5 also associates with Ste4, the beta subunit of a heterotrimeric guanine nucleotide-binding protein, potentially linking receptor activation to stimulation of the MAPK cascade [4].
• STE4 encodes the beta-subunit of a heterotrimeric guanine nucleotide-binding protein (G protein) that is an early and essential component of the pheromone signal transduction pathway [5].

Biological context of STE4

• Mutations in STE4, 5, 7, and 11 partially reduced the number of binding sites, but this reduction was not sufficient to explain the loss of responsiveness; the products of these genes appear to affect postreceptor steps of the response pathway [6].
• The slow-growth phenotype manifested by cells carrying STE5Hyp alleles was enhanced by the sst2-1 mutation; this effect was eliminated in ste4 mutants [7].
• The membrane distribution of Ste4p was unaffected by the ste2 mutation or by down-regulation of the cell-surface receptors [8].
• In order to identify amino acid residues of Ste4p involved in receptor recognition and/or receptor-G protein coupling, we employed random in vitro mutagenesis and a genetic screening to isolate mutant Ste4p subunits with altered pheromone response [9].
• We generated a plasmid library containing randomly mutagenized Ste4 ORFs, followed by phenotypic selection of ste4p mutants by altered alpha pheromone response in yeast cells [9].

Anatomical context of STE4

• We found that the products of the STE4 and STE18 genes are stably associated with plasma membrane as well as with internal membranes and that 30% of the protein pool is not tightly associated with either membrane fraction [8].

Associations of STE4 with chemical compounds

• This delta C6 mutant acts as a dominant negative because it blocks the growth arresting effect obtained by over-expression of STE4 [10].
• Here we demonstrate that Ste4 and Ste5 activate Kss1 during IG and in response to multiple stimuli including butanol [11].
• Ste4 contains a leucine zipper and is capable of homotypic interaction [12].

Physical interactions of STE4

• The two-hybrid system revealed that Ste4p interacts with Cdc24p [13].
• The identification of a ste18 mutant indicated that this screen could identify proteins that interact directly with Ste4p [14].
• In cells with a constitutively activated pheromone response pathway, epitope-tagged Ste4p was coimmunoprecipitated with Ste5p [15].
• Consistent with these genetic observations, the suppressing form of Syg1p can interact with the STE4 gene product, as determined by a two-hybrid assay [16].
• Mutation of the Q323 residue of Gpa1p resulted in constitutive activation of the pheromone response pathway and eliminated the ability to interact with Ste4p, consistent with a defect in GTPase activity [17].

Regulatory relationships of STE4

• GPA1 hyperexpression suppressed the phenotype of STE4 overexpression [18].
• Overexpression of the STE4 gene product also suppressed the sterility of cells defective in the mating pheromone receptors encoded by the STE2 and STE3 genes [19].
• However, STE18 was essential for the response, since overexpression of STE4 was unable to activate a response in a ste18 null strain [18].

Other interactions of STE4

• The cross talk in hog1 mutants induced multiple responses of the pheromone response pathway: induction of a FUS1::lacZ reporter, morphological changes, and mating in ste4 and ste5 mutants [20].
• However, the phenotypes of the STE5Hyp mutations were less pronounced in ste4 and ste18 mutants, suggesting that the STE5Hyp-generated signal partially depends on the proposed G beta gamma complex [7].
• Others have provided genetic evidence consistent with an interaction between the SCG1 (GPA1) and STE4 gene products [21].
• This activation was dependent on Ste4p and Ste18p and partially dependent on Ste20p [14].
• We also found, in a pull-down assay, that Rho1 associates with GST-Ste4 and that Rho1 is localized to the neck and tip of mating projections [22].

Analytical, diagnostic and therapeutic context of STE4

• A haploid-specific interaction between the amino terminus of Ste5p and the G protein beta subunit Ste4p was also detected in a two-hybrid assay, and the product of a signaling-defective allele of STE4 was defective in this interaction [15].
• Sequence analysis of the STE4 locus in the relevant mutant strains revealed seven novel STE4 alleles, each of which was shown to disrupt proper regulation of the pheromone response [23].
• In this study we used site-directed mutagenesis to create two phosphorylation null (Pho-) alleles of STE4: ste4-T320A/S335A and ste4-T322A/S335A [24].
• Conversely, overproduction of Sst2 markedly enhanced the rate of recovery from pheromone-induced arrest in the long-term halo bioassay and detectably dampened signaling in a short-term assay of pheromone response (phosphorylation of Ste4, Gbeta subunit) [25].

References