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Articles by G Kawai
Total Records ( 2 ) for G Kawai
  F Waheed , P Speight , G Kawai , Q Dan , A Kapus and K. Szaszi
 

Plasma membrane depolarization activates the Rho/Rho kinase (ROK) pathway and thereby enhances myosin light chain (MLC) phosphorylation, which in turn is thought to be a key regulator of paracellular permeability. However, the upstream mechanisms that couple depolarization to Rho activation and permeability changes are unknown. Here we show that three different depolarizing stimuli (high extracellular K+ concentration, the lipophilic cation tetraphenylphosphonium, or l-alanine, which is taken up by electrogenic Na+ cotransport) all provoke robust phosphorylation of ERK in LLC-PK1 and Madin-Darby canine kidney (MDCK) cells. Importantly, inhibition of ERK prevented the depolarization-induced activation of Rho. Searching for the underlying mechanism, we have identified the GTP/GDP exchange factor GEF-H1 as the ERK-regulated critical exchange factor responsible for the depolarization-induced Rho activation. This conclusion is based on our findings that 1) depolarization activated GEF-H1 but not p115RhoGEF, 2) short interfering RNA-mediated GEF-H1 silencing eliminated the activation of the Rho pathway, and 3) ERK inhibition prevented the activation of GEF-H1. Moreover, we found that the Na+-K+ pump inhibitor ouabain also caused ERK, GEF-H1, and Rho activation, partially due to its depolarizing effect. Regarding the functional consequences of this newly identified pathway, we found that depolarization increased paracellular permeability in LLC-PK1 and MDCK cells and that this effect was mitigated by inhibiting myosin using blebbistatin or a dominant negative (phosphorylation incompetent) MLC. Taken together, we propose that the ERK/GEF-H1/Rho/ROK/pMLC pathway could be a central mechanism whereby electrogenic transmembrane transport processes control myosin phosphorylation and regulate paracellular transport in the tubular epithelium.

  G Kawai and S. Yokoyama
 

The late Prof. Tatsuo Miyazawa was an outstanding physical chemist, who established a number of spectroscopic methods to analyse the structures of proteins, peptides and nucleotides, and used them to understand molecular functions. He developed an infrared spectroscopic method to quantitatively analyse the secondary structures, -helices and β-strands, of proteins. He successfully utilized nuclear magnetic resonance (NMR) methods to determine the conformations of peptides and proteins, particularly with respect to the interactions with their target molecules, which served as a solid basis for the wide range of applications of NMR spectroscopy to life science research. For example, he found that physiologically active peptides are randomly flexible in solution, but assume a particular effective conformation upon binding to their functional environments, such as membranes. He also used NMR spectroscopy to quantitatively analyse the conformer equilibrium of nucleotides, and related the dynamic properties of the modified nucleosides naturally-occurring in transfer ribonucleic acids (tRNAs) to their roles in correct codon recognition in protein synthesis. Furthermore, he studied the mechanisms of protein biosynthesis systems, including tRNA and aminoacyl-tRNA synthetases. Inspired by the structural mechanism of amino acid recognition by aminoacyl-tRNA synthetases, as revealed by NMR spectroscopy, he initiated a new research area in which non-natural amino acids are site-specifically incorporated into proteins to achieve novel protein functions (alloprotein technology).

 
 
 
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