On Aug. 7, the field of signal transduction and, indeed, our entire scientific community lost one of its giants, Tony Pawson. Pawson made seminal contributions to our understanding of how receptor tyrosine kinases implement and propagate specific signals throughout the cell. The best known of these contributions was the discovery of the Src homology-2 (SH2) domain and the insight that this domain binds phosphotyrosine, thereby enabling the formation of modular multiprotein signaling complexes.
Anthony James Pawson was born in Maidstone, England, on Oct. 18, 1952. His father was an accomplished athlete (a 1952 soccer Olympian and champion cricket player). His mother, a high-school biology teacher, sparked her son’s interest in science.
Tony Pawson received his early education at Winchester College, an elite English public school. From there he moved on to Clare College at Cambridge University, graduating in 1973. He completed his Ph.D. in 1976 in the laboratory of Alan Smith at the Imperial Cancer Research Fund. There he studied how the proteins of the Rous sarcoma virus mediate oncogenesis and promote retroviral replication.
Pawson continued to work on transforming retroviruses during his postdoctoral training in Steven Martin’s laboratory at the University of California, Berkeley. Prompted by the discovery that the RSV transforming protein v-Src was a tyrosine kinase, Pawson discovered that the transforming protein of the Fujinami avian sarcoma virus, v-Fps, was also a tyrosine kinase.
In 1981, Pawson became an assistant professor at the University of British Columbia in Vancouver. He continued his studies of v-Fps. He and his colleagues discovered that a noncatalytic region of v-Fps was subject to noncatalytic insertions and that this noncatalytic region in v-Fps was structurally similar to a noncatalytic portion of v-Src. He dubbed this region Src homology-2 (SH2 — with SH1 being the catalytic domain). A third conserved region, the SH3 domain, was discovered later. SH2 and SH3 domains then were found to exist in a vast number of signaling proteins. Of note, several proteins, including the Crk oncogene, appeared to consist solely of SH2 and SH3 domains.
While the importance of tyrosine phosphorylation was evident from cell biological findings, the discovery of the SH2 domain was pivotal in defining how phosphotyrosine signals. Again, Pawson was at the center of these findings. In a particularly important advance, he and others showed that isolated SH2 domains bind phosphotyrosine, thereby permitting the recruitment of SH2-containing proteins to autophosphorylated tyrosine kinases — including receptor tyrosine kinases — and other phosphotyrosine-containing proteins. A major example of this sort of signaling was discovered in 1992 in Pawson’s laboratory. Thus, the SH2-containing scaffold protein Shc bound to phosphotyrosines on the EGF receptor. This leads, in turn, to tyrosine phosphorylation of Shc. The phosphotyrosines on Shc then recruit another SH2 adapter protein, Grb2, the SH3 domains of which enable formation of a stable complex with the Ras guanine nucleotide exchanger Sos. This process of modular protein assembly brings Sos to the plasma membrane, where Ras resides, and promotes Ras GDP/GTP exchange and activation. Activated GTP-Ras then recruits several protein kinase signaling pathways, including the ERK MAP kinases.
In 1985, Pawson moved to the Samuel Lunenfeld Research Institute of Mount Sinai Hospital in Toronto (now the Lunenfeld-Tanenbaum Research Institute), rising to serve as director from 2000 to 2005. His influence on Canadian science during this time cannot be overestimated. In addition to achieving the pivotal discoveries noted above, he recruited numerous outstanding scientists to the institute, promoted the incorporation of new technologies into signaling research (notably proteomics) and founded biotechnology companies. He was also the recipient of several Canadian science awards — including, in 2006, the Companion of Honor.
Pawson was also the recipient of numerous international awards, including the Gardiner Award, the Wolf Prize and the Kyoto Prize. He was on the short list to win the Nobel Prize.
Important advances continued to emerge from the Pawson laboratory. Indeed, in July of this year, the laboratory described a detailed analysis of the diversity of Shc signaling at different time points after EGF receptor engagement. The group used mass spectrometry and other emerging technologies to show that Shc forms a dynamic series of transient tyrosine phosphorylation and protein-interaction events to control the pleiotropic cellular responses to EGF.
With the sudden and untimely passing of such a great scientist, one is left wondering what might have been — what important discoveries might have been made and which young scientists might have emerged from his laboratory, trained and encouraged to go on to greatness themselves. Given that the transition of discoveries in biomedical science from bench to bedside takes many years, this loss becomes still more unfortunate.
In taking the long view, it is important to remember that Pawson’s seminal discoveries arose from decades of research that began with studies of a virus that affects chickens and culminated with important breakthroughs directly relevant to human disease. Pawson himself made this insightful remark at the time he received the Kyoto Prize: “Governments increasingly want to see immediate returns on the research that they support. But it is worth viewing basic science as a long-term investment that will yield completely unexpected dividends for humanity in the future. I believe that this progress underscores the importance of giving free rein to human inventiveness.” We are saddened by the loss of such a figure but inspired by the legacy of outstanding inventiveness exemplified by Tony Pawson.
John M. Kyriakis (firstname.lastname@example.org) is an associate editor for The Journal of Biological Chemsitry.