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Profile of Philip Cohen Profile of Philip Cohen ir Philip Cohen, a biochemist like switch its activity on or off, but it elected as a foreign associate to can also stabilize a protein or allow it to the National Academy of Sci- be degraded or allow it to move from ences in 2008, remembers the one part of the cell to another part of Smoment in his distinguished career the cell.’’ when his studies in cell signaling and During his time in Seattle, Cohen pri- protein phosphorylation took off. The marily worked on glycogen phosphory- moment arrived during a 1978 seminar lase. The subject began to draw more of given by Thomas Vanaman at the Uni- his attention after he left Fischer’s labo- versity of Dundee (Dundee, Scotland, ratory and took a position in the newly UK). At that time, Cohen had been founded biochemistry department at the working on the first kinase to be stud- University of Dundee in 1971. ied, phosphorylase kinase, which helps After his first eureka! moment when to regulate the breakdown of glycogen. he discovered the connection between Cohen had purified the kinase to study calmodulin and phosphorylase kinase, how it was regulated by cAMP and cal- Cohen went on to discover other calmod- cium, but he could not untangle the ulin-dependent enzymes, including the mechanisms by which calcium activated first calcium- and calmodu- it. That afternoon, Vanaman spoke lin-dependent phosphatase, calcineurin. about work he had done on calmodulin, Calcineurin was later shown by others a calcium-binding protein and a known to activate a transcription factor in T intermediary in calcium-regulated pro- cells by removing phosphate groups, cesses. Vanaman’s descriptions of cal- which then up-regulates the production modulin—its small size and heat stabil- of interleukin-2 and prompts T cell ity—gave Cohen a better idea of the proliferation. perplexing faint blue smear that he had Philip Cohen These immune-system effects took on observed at the bottom of his poly- increased medical importance when re- acrylamide gels. Cohen had been so searchers discovered that the protein focused on the massive kinase subunits led Cohen to pursue a career in bio- was the target of the immunosuppres- controlled by cAMP that he had chemistry at University College London sant drug cyclosporine. Used mostly to missed the small protein that ran off (London, UK). ‘‘Somehow I thought prevent transplant rejection, cyclospor- the end of the gel. that biochemistry must be a cross be- ine had been on the market for 8 years Rushing back to his laboratory after tween chemistry and bird-watching,’’ before researchers discovered that it Vanaman’s seminar, Cohen prepared a Cohen said, recalling that the subject targeted calcineurin. different type of gel and identified a initially did not hold much interest for A Multiplicity Uncovered small band ahead of the dye front—a him. band that appeared even after the sam- Only when he began his first indepen- Cohen’s studies on phosphorylase ki- ple had been boiled, indicating the com- dent laboratory projects in his third year nase had unexpectedly led him to dis- ponent was heat-stable. ‘‘Then I knew at the university did he decide to con- cover that it was phosphorylated at mul- what the answer was going to be,’’ Co- tinue with biochemistry. He discovered tiple sites. The other enzymes known to hen said. ‘‘This must be the missing that, ‘‘with my own hands, I could actu- be regulated by phosphorylation only component.’’ Shortly after, Cohen’s hy- ally find out something that no one had had one site. ‘‘It seemed to me an extra pothesis was confirmed: calmodulin me- found out before.’’ sophistication in the control system,’’ he diated the action of calcium ions on Cohen graduated from University said. phosphorylase kinase. College London with his Ph.D. in bio- He stumbled across glycogen synthase Cohen has remained at the University chemistry in 1969, where he worked in a literature review, and suspected of Dundee since 1971 and has worked with Michael Rosemeyer in physical that reports of a single phosphorylation on many areas of signal transduction, protein chemistry to identify the sub- site on the enzyme were wrong. As he from protein phosphorylation to ubiq- units of glucose-6-phosphate dehydroge- investigated the protein, he found that uitination. His inaugural article, pub- nase. He then accepted a postdoctoral not only did glycogen synthase have sev- lished in a recent issue of PNAS, identi- fellowship at the University of Washing- eral phosphorylation sites, each phos- fies the phosphorylation sites on Pellino ton (Seattle, WA) with future Nobel phate group was introduced by a sepa- that activate this signaling protein that Laureate Edmond Fischer, examining rate kinase. ‘‘So the more we studied controls ubiquitination events in the in- protein phosphorylation and the regula- this enzyme, actually, the more compli- nate immune system (1). tion of glycogen metabolism. cated it became,’’ Cohen said. ‘‘We At the time, protein phosphorylation eventually found it was phosphorylated In the Beginning was thought to be a specific mechanism on no less than 9 different sites by 7 Born just outside London in 1945, Philip confined to glycogen metabolism. In different kinases.’’ Cohen spent much of his childhood ex- fact, the process is a near-universal reg- Cohen and his team identified a third ploring the woods around his house. His ulatory system that evolved in early pro- kinase, glycogen synthase kinase 3 father worked as a printing ink technol- karyotes that regulates protein function (GSK3), and showed that the phosphate ogist, designing color inks for use in sev- in a simple, flexible, and—perhaps most eral of Britain’s major publications. The importantly—reversible process. ‘‘When This is a Profile of a recently elected member of the National combination of an interest in natural you attach a phosphate to a protein,’’ Academy of Sciences to accompany the member’s Inaugu- history and an aptitude for chemistry Cohen said, ‘‘it can do something simple ral Article on page 4584 in issue 12 of volume 106. 7692–7694 ͉ PNAS ͉ May 12, 2009 ͉ vol. 106 ͉ no. 19 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0903588106 Downloaded by guest on September 27, 2021 PROFILE groups added by GSK3 in muscle cells nases (MAPKs) played a role in this MAPK pathway works to prevent the were removed within minutes after stim- process. The classical MAPK signal activation of MAP2K1 by the protein ulating the cells with insulin. So, Cohen transduction pathway links extracellular kinase Raf. figured, either the insulin inactivated signals (mitogens) to downstream intra- These collaborations opened Cohen’s GSK3, or it turned on a phosphatase cellular effects. Although the MAPK eyes not just to the therapeutic poten- that removed the phosphate groups, signaling cascade turned out not to re- tials of kinase inhibitors and their use as which activated glycogen synthase. late specifically to insulin signaling, as reagents in basic research, but also to He later established how insulin af- Cohen had initially thought, it played a the development of a relationship be- fected GSK3 through a series of chemi- role in cellular growth and proliferation. tween industry and academia. Between cal reactions regulated by phosphoryla- His work on MAPK signaling led to 1996 and 1998, Cohen persuaded 6 tion. His research group showed that the identification and characterization of pharmaceutical companies to help sup- protein kinase B (PKB, also called Akt) MAP kinase kinase 1 (MAP2K1), which port his signal transduction unit, part of switched off GSK3 activity and with integrates the extracellular signals by the protein phosphorylation unit he Dario Alessi discovered that PKB was phosphorylating MAP kinase. Cohen’s founded at the University of Dundee. activated by 3-phosphoinositide-depen- group then used a cell line whose stimu- The corporate collaboration, which dent protein kinase 1 (PDK1). These lation by nerve growth factor (NGF) has recently been renewed for a third series of studies explained how insulin, activated MAPK signaling and caused time, ‘‘led to the development of a num- acting through the ‘‘second messenger’’ the cells to differentiate into a neuronal- ber of new technologies, like kinase pro- phosphatidylinositol (3,4,5)-trisphos- like phenotype. The effect of NGF con- filing, that have helped to accelerate the phate, activated glycogen synthase in trasted with previous studies showing development of specific inhibitors of muscle (2). that epidermal growth factor (EGF), kinases, and to a lot of useful new tools As he continued to work on glycogen which also activates the MAPK signaling and reagents for the cell signaling com- metabolism, he also started to look at pathway, does not cause neuronal munity,’’ Cohen said. protein phosphorylation more globally, differentiation. This research has resulted in the de- classifying the various protein phospha- velopment of new therapeutic agents. tases involved in different cellular pro- cesses. In 1983, he published a series of ‘‘With my own hands, The ‘‘Next Big Thing’’ 7 articles that examined the different A few years ago, Cohen switched his phosphatases, culminating in a review in I could find out research to the study of the innate im- Science that defined 4 different classes mune system, which led him to focus on of protein phosphatases (3). something no one a new area of cellular signaling: ubiq- ‘‘Until we actually carried out that uitination. Just as phosphorylation in- study,’’ Cohen said, ‘‘different people in had found before.’’ volves the reversible attachment of the world were all working on what they phosphate groups to enzymes, ubiquiti- thought were different phosphatases, nation reversibly attaches to enzymes a each of which removed phosphate from ‘‘I found that there was an important small protein called ubiquitin.
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