PubMed · 14311706
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H LOEWE. 1965-02-11. [MEMBRANE SYSTEMS AS A STRUCTURAL BASIS OF CELLULAR FUNCTION].. https://pubmed.ncbi.nlm.nih.gov/14311706/
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Yeasts are beneficial microorganisms for human society and are utilized for academic and industrial purposes. For academic purposes, S. cerevisiae is a well-investigated model for studying eukaryotic cellular processes. For industrial purposes, S. pastorianus, which has a hybrid genome of S. cerevisiae and S. eubayanus, has been served for lager beer production. During fermentation, S. pastorianus produces ~7% of EtOH, which induces plasma membrane (PM)/cell wall stress in yeast. Therefore, S. pastorianus may experience PM stress and adapt to the self-forming environment during fermentation. However, how yeast adapts to PM stress remains unclear. Here, we investigated the temporal cellular responses of S. cerevisiae and S. pastorianus during adaptation to PM stresses by time-resolved mRNA-seq analysis. Our data showed different transcriptional phenotypes between S. cerevisiae and S. pastorianus during adaptation. The results may reflect the distinct nature of the two yeasts that have evolved in different nutritional environments. The dataset presented here would provide a promising resource for studying the characteristic nature of these differentially domesticated yeasts upon PM stresses.
The membrane redistribution and phosphorylation of focal adhesion kinase (FAK) have been reported to be important for cell migration. We previously showed that Lysophosphatidic acid (LPA) induced FAK membrane redistribution and autophosphorylation in ovarian cancer SK-OV3 cells and the signaling pathway consisting of Gi-Ras-MEKK1 mediated LPA-induced FAK membrane redistribution but not FAK autophosphorylation. We also showed that the disruption of the Gi-Ras-MEKK1 pathway led to a significant reduction in LPA-stimulated cell migration. These findings raised the question of whether LPA-induced FAK autophosphorylation was required for LPA-stimulated cell migration and what signaling mechanism was involved in LPA-induced FAK autophosphorylation. In this study, we expressed the membrane anchored wild-type FAK (CD2-FAK) in SK-OV3 cells and found that the expression of CD2-FAK greatly rescued LPA-stimulated cell migration in Gi or Ras-inhibited cells. However, Gi inhibitor pertussis toxin or dominant-negative H-Ras still significantly inhibited LPA-stimulated cell migration in cells expressing the membrane anchored FAK containing a mutation in the autophosphorylation site [CD2-FAK(Y397A)]. These results suggest that FAK autophosphorylation plays a role in LPA-stimulated cell migration. With the aid of p115RhoGEF-RGS, G12 and G13 minigenes to inhibit G12/13, we found that the G12/13 pathway was required for LPA-induced FAK autophosphorylation and efficient cell migration. Moreover, LPA activated RhoA and Rho kinase (ROCK) in a G12/13-dependent manner and their activities were required for LPA-induced FAK autophosphorylation. However, Rho or ROCK inhibitors displayed no effect on LPA-induced FAK membrane redistribution although they abolished LPA-induced cytoskeleton reorganization. Our studies show that the G12/13-RhoA-ROCK signaling pathway mediates LPA-induced FAK autophosphorylation and contributes to LPA-stimulated cell migration.
Reverse chemical genetics is an emerging technique that makes use of small molecule inhibitors to characterize how a protein functions. In this regard, we have developed an NMR-based approach (SAR by ILOEs) that enables the identification of high affinity ligands for a given protein target without the need of a specific assay. Our approach is of general applicability and could result very powerful in reverse chemical-genetics studies, target validation, and lead discovery. We report a recent application on the design and synthesis of compounds that inhibit protein-membrane interactions.