Tony Pawson: Modular protein domains and the links to intracellular signaling

It is with great sorrow that I write that Tony Pawson, a good friend, great colleague, generous collaborator, and brilliant scientist, died at the age of 60 on August 7, 2013. Tony was a trail-blazer and innovator in his studies of the mechanisms underlying intracellular signaling. His work had an enormous impact on our understanding of how external cellular stimuli lead to the activation of intracellular signaling pathways. Tony focused on how protein interactions are initiated, regulated, and integrated. His work had and will continue to have impact on our understanding of pathogenesis and toward our development of therapies for many diseases, including cancer, neurological diseases, diabetes, and autoimmunity.

Tony Pawson 1952–2013.

Anthony James Pawson was born on October 18, 1952 in Maidstone, County Kent, England. His mother, a high school biology teacher and botanist, inspired Tony’s interest in the natural world that surrounded him. His father, the elder Tony Pawson, was an inspired athlete and sportsman, having played for the Olympic soccer team from England at Helsinki the year the younger Tony was born. His father also won the world fly-fishing championship at the age of 66. From his father, Tony learned to communicate clearly, to compete effectively, and to get things done. Tony also acquired a long-lasting love of fly-fishing, which was often revealed when he ambled off with his fishing rod and gear during a free afternoon at a Federation of American Societies for Experimental Biology or Gordon summer research conference.

Tony believed that his interest in science was sparked at an early age. An inspirational high school biology teacher, Michael Baron, introduced Tony to biochemistry, physiology, and early scientific investigation. These interests were reinforced while Tony attended Cambridge University, where he worked with Tim Hunt. Hunt advised him to do his doctorate at the Imperial Cancer Research Fund (ICRF), where he worked with Alan Smith on mechanisms by which retroviruses propagate. While at the ICRF, Tony married his beloved wife of more than 30 years, Maggie, who died two years ago. Tony also met Steve Martin at the ICRF, who had recently shown that the Src gene endowed upon the Rous sarcoma virus its cancer-causing ability. Inspired by Martin’s work, Tony joined Martin’s laboratory at the University of California at Berkeley for his postdoctoral training. By then, Src had been shown to be a tyrosine kinase. At Berkeley, Tony began to study Src and developed a strong interest in cancer-causing genes and their relationship to tyrosine phosphorylation. This experience led him to study the v-Fps gene of the Fujinami avian saroma virus, which also encoded a tyrosine kinase.

In 1981, Tony moved to the University of British Columbia in Canada for his first independent position as an Assistant Professor. He continued to study the Fps protein over the next several years. Using site-directed mutagenesis, Tony’s laboratory was able to identify three distinct regions of the Fps protein important for its transforming ability. One region was the tyrosine kinase domain. However, Tony noted that one of the other regions, upstream of the kinase domain, had remarkable sequence identity to regions in the Src protein as well as in another protein, Abl, which also had tyrosine kinase activity. Tony defined the homologous region to be about 100 amino acids and dubbed it the SH2 domain (the kinase domain was the SH1 domain).

Tony moved to the Samuel Lunenfeld Research Institute in Toronto, where he worked for the past 28 years and served as its Director from 2000 to 2005. In 1990 in a paper published in PNAS (1), Tony and his group showed that the SH2 domain could be expressed as an independent protein domain that had the ability to bind to tyrosine phosphorylated proteins. This seminal paper led Tony on a long, productive, and influential career that thematically centered on the concept that signaling proteins use modular protein domains, which are expressed singly or are linked together within a protein, to orchestrate interactions between proteins as well as between proteins and lipids. These modular domains, now consisting of perhaps 80 different types, have different specificities and affinities. Moreover, each of these types of domains has many different family members. For example, there are more than 110 SH2 domains, each of which has specificity for tyrosine phosphorylated residues within particular amino acid sequences; similarly, there are more than 300 SH3 domains, which recognize proline-containing sequences. Such modules can be combinatorially assembled within proteins that contain enzymatic functions, such as tyrosine kinase activity, or may exist in proteins without enzymatic activity. The latter proteins are called adaptors. Adaptors seemed to fascinate Tony by virtue of their ability to serve only as links between proteins in signaling networks that could be regulated. Thus, through the presence of different combinations and different numbers of modular interaction domains, incredible diversity of functional activities and of intermolecular interactions can be achieved. Tony’s work and conceptual advances on these interaction modules have had broad impact on many fields within biology and medicine.

Throughout his career, Tony used whatever technologies were needed to study the role of the modular interaction domains within signaling networks to understand complex cell behavior. He used detailed biophysical and biochemical techniques, carried out genetic manipulations in model organisms, and pioneered new technologies in proteomics and bioinformatics to study signaling events during cell–cell interactions. Importantly, Tony always seemed to extend his latest fundamental observations to more physiologic contexts in model organisms or in human diseases.

An invited speaker at most signaling meetings, Tony was an enthusiastic and engaging lecturer and always seemed to have a new and interesting scientific story to tell. The sparkle in his eye foreshadowed that something exciting was about to be revealed. Importantly, Tony frequently found a way to spin the tale in the context of work done by others in the audience as a way to engage and also to humbly acknowledge those whose work preceded his. Tony was especially interested in young scientists and found opportunities to pat them on the back and give them encouragement. Tony had a great sense of humor, often at his own expense. His classic chuckle could be frequently heard during his lecture or around a table at a meal. Tony made signaling meetings so much more enjoyable and interesting. He was such an important speaker and participant because he inspired new ways of looking at scientific conundrums. There will be a void at signaling meetings without his keen insight, sharp wit, and collegiality.

Tony accomplished much during his shortened career. The importance of his work led to many honors, including the Kyoto Prize, the Gairdner Award, and the Wolf Prize, as well as election as a foreign associate of the National Academy of Sciences. His discoveries and insights had an enormous impact in many fields of biology and will continue to influence thinking and work in the fundamental sciences, as well as in the biomedical sciences far into the future.

Tony Pawson will be very sorely missed by his family, friends, and colleagues. However, Tony enriched our lives in many ways. We will have many cherished memories of our times together and the lessons he taught us. We will have a large number of inspirational published papers on which to rely. His many outstanding trainees will carry his work forward. Although his life was cut too short, the knowledge base that Tony Pawson leaves behind for us will provide a scientific framework upon which to build new hypotheses and paradigms.