Yasutomi Nishizuka's Discovery of Protein Kinase C

Abstract

Yasutomi Nishizuka (1932–2004) was born in Ashiya-city, Japan. He attended Kyoto University and obtained his M.D. in 1957 and his Ph.D. in 1962, working with Journal of Biological Chemistry (JBC) Classic author Osamu Hayaishi (1). He then spent a year as a postdoctoral fellow at Rockefeller University with Fritz Lipmann (also featured in a JBC Classic (2)) before returning to Kyoto University to resume work with Hayaishi. During this time, Nishizuka studied the biosynthesis of nicotinamide adenine dinucleotide (NAD), the involvement of GTP in ribosomal protein translation, and ADP-ribosylation by diphtheria toxin. Yasutomi Nishizuka In 1969, Nishizuka accepted the position of full professor and head of the department of biochemistry at the Kobe University School of Medicine. There, Nishizuka became interested in the role of protein kinases in the regulation of cell functions. This led to his discovery of a novel protein kinase, which he published in the first paper reprinted here as the JBC Classic. As Nishizuka reported in that paper, he and his colleagues partially purified the kinase from bovine cerebellum. They found that the enzyme was capable of phosphorylating histone and protamine and that it probably was produced from its precursor protein by a limited proteolytic reaction. The detailed properties of the proenzyme and its conversion to active protein kinase were reported in a subsequent JBC paper (3). Nishizuka named this new enzyme “protein kinase C (PKC).” A paper published by Nishizuka two years later in the JBC (4) showed that PKC was activated without limited proteolysis by a membrane-associated factor in the presence of a low concentration of Ca2+. In 1980, he published another paper in the JBC (5) showing that the membrane-associated factor was diacylglycerol, which suggested that the lipid could be a novel second messenger generated by receptor-stimulated phosphoinositide hydrolysis. Nishizuka validated this idea by showing that treating platelets with a combination of a Ca2+ ionophore and membrane-permeant short chain diacylglycerol mimicked stimulation by the aggregating agent thrombin (6). This discovery was a major advance in the understanding of cell signaling. Nishizuka and his colleagues then discovered that PKC is the biological target of tumor-promoting phorbol esters. At that time, it was well known that croton oil augmented carcinogenesis when it was applied at weekly intervals to the skin of mice in conjunction with a very dilute solution of benz[a]pyrene in acetone. The oil contained phorbol ester, a powerful tumor promoter, and caused a wide variety of cellular responses that were similar to those seen with hormones. Nishizuka speculated that the phorbol ester was producing diacylglycerol to activate PKC. However, upon further investigation, he realized that the phorbol ester contained a diacylglycerol-like structure and thus might activate PKC directly. In a series of experiments, published in the second JBC Classic reprinted here, Nishizuka was able to show that the phorbol ester activated PKC directly. This discovery showed that PKC was important for cell proliferation and cancer. It also established the use of phorbol esters as crucial tools for the manipulation of PKC activation in intact cells, eventually allowing the elucidation of the wide range of cellular processes regulated by this enzyme. This research laid the foundation for an enormous number of studies on the complex PKC family, many of them from Nishizuka's group. In 1975, Nishizuka became president of the University of Kobe, a position that he held until 2001. He received numerous awards and honors for his research, including the Gairdner Foundation International Award (1988), the Alfred P. Sloan Jr. Prize (1988), the Japan Order of Culture (1988), the Albert Lasker Basic Medical Research Award (1989), the Kyoto Prize (1992), the Wolf Prize in Medicine (1995), the Jimenez Diaz Award (1995), and the Schering Prize (1995). He also served as a foreign member and honorary fellow of various academies, including the National Academies of Science, the Royal Society, l'Academie des Sciences, die Deutsche Akademie der Naturforscher Leopoldina, le Real Academia de Ciencias, the Asiatic Society, and the Japan Academy.1