Q: Your roots in phosphatase research run pretty deep, don’t they?
A: I think it is fair to say that, yes. I have always been interested in protein phosphorylation and, being naturally a bit contrary, the phosphatases held a greater attraction for me than the kinases. When I joined Philip Cohen’s lab for my PhD, I focused on the phosphatases from day 1, initially working to show that calcineurin, then known as a major calmodulin-binding protein in brain, has intrinsic phosphatase activity. I joined Eddy Fischer’s lab at the University of Washington in Seattle for my postdoctoral work, and we decided to take a run at the protein tyrosine phosphatases (PTPs), about which very little was known at the time. I completed the first purification of a PTP, isolating PTP1B from human placenta, and with my collaborators identified CD45 as a prototype for a Receptor-like PTP, analogous to the situation with receptor protein tyrosine kinases. We, and others, went on to show that the PTPs were a large family of enzymes that, like the kinases, play a critical, direct role in the regulation of cell signaling.
Given the fundamental importance of PTPs in signaling, such as PTP1B and its key role in the response to insulin, there has been great interest in targeting these enzymes therapeutically. Due to the chemistry of PTP catalysis and architecture of the active site, drug substances that target the catalytic center were highly charged and not amenable to the need for an oral formulation. These initial setbacks resulted in an exodus from programs tasked with developing phosphatase-targeted therapeutics, which was quite remarkable and, in hindsight, a little hard to comprehend. Nevertheless, my lab embraced the challenge, and we have focused on the protein phosphatases ever since.
