Dr. Woodgett is the Director of Research at the Samuel Lunenfeld Research Institute of Mount Sinai Hospital in Toronto, Ontario, Canada. In the interview below, he talks with us about his highly cited research.

Please tell us a little about your research and educational background.

I've always been interested in signaling pathways and their role in various diseases, particularly cancer and diabetes. I'm from the UK originally and trained and worked with several great signal transduction scientists including Philip Cohen (Ph.D., Dundee), Tony Hunter (see also ¦ see also (postdoc, Salk Institute), and Mike Waterfield (first independent position, London).

I've been in Toronto for over 15 years, first at the Ontario Cancer Institute and for the past three years at the Lunenfeld, which, with brilliant people like Tony Pawson, Jeff Wrana, and Frank Sicheri, as well as young stars like Dan Durocher, Helen McNeill, and Anne-Claude Gingras, is a scientific mecca for signal transduction. It's a small institute (32 investigators) but incredibly interactive, hence I've benefited greatly by collaborating with scientists like Andras Nagy, Dan Drucker, and Jim Dennis in rapidly developing new ideas.

What do you consider the main focus of your research, and what drew your interest to this particular area?

Everyone in the lab works on some aspect of signaling in disease with type-2 diabetes, breast cancer, and stem-cell fate determination being our core interests. We tend to focus on protein-serine kinases since these seem to be the command and control points in cells, and it's gratifying to see how many have become important therapeutic targets. Despite the focus on protein kinases, most of our work depends on cell biology and mouse genetics (our single largest research expense).

Your most-cited paper in our database's field of Molecular Biology & Genetics (Hoeflich KP, et al., "Requirement for glycogen synthase kinase-3 beta in cell survival and NF-kappa B activation," Nature 406[6791]: 86-90, 6 July 2000), as well as many of your other highly cited papers, deal with glycogen synthase kinase-3. Would you talk a little bit about this aspect of your research?

It's somewhat scary, but this protein kinase figured prominently in my Ph.D. thesis. I've known it longer than my wife! You might think spending 27 years on a single enzyme is excessive or, perhaps, obsessive, but this kinase throws out surprises all the time. It was first identified by Phil Cohen's group as a key regulator of glycogen synthase, the rate-limiting enzyme of glycogen synthesis. I cloned the GSK-3 genes in 1990 and within two weeks of that publication two other papers appeared from fly geneticists who'd cloned a key gene involved in developmental patterning. The sequence showed their gene was GSK-3. That was our first clue that there was more to this kinase than sugar metabolism. Since then, it's been a case of one unexpected finding leading to the next. That said, this kinase sits downstream of five major signaling systems and targets over 50 regulatory proteins including proto-oncogenes and a slew of transcription factors. It is clearly "well connected."

The two genes that encode this kinase overlap in many functions so our most recent work has focused on understanding the tissue-specific and isoform-specific functions. We've also found some remarkable biological effects when both genes are inactivated in particular cell types, so this kinase has a few more surprises up its sleeve. What's perhaps most interesting from a disease standpoint is that different levels of GSK-3 activity are associated with quite different phenotypes and disorders. This has therapeutic implications as well as insights into how cells partition and specialize their rather generic signaling pathways.

Several of your highly cited papers deal with stress-activated protein kinase pathways. What is the importance of these pathways?

Good question, because we still don't fully appreciate the answer! The body of work on stress-activated protein kinases (now better known as JNKs) was a result of a long and productive collaboration with Joe Avruch and John Kyriakis in Boston. We naively thought the SAPK/JNK pathway would mediate the appropriate transcriptional response to stress-inducing stimuli such as apoptosis or growth arrest since the primary target of these kinases was c-Jun/AP1.

However, in subsequent work from many labs, it has become clear that the pathway rarely, if ever, works alone and the consequences of its activation are largely dependent on context. Dissecting the specific physiological functions has been complicated by the fact that the agonists of this pathway induce many other systems. We think we have a handle on this at long last via generation of a constitutively active mutant, which I hope will allow us to isolate the specific functions of the SAPK/JNKs.

How has this field changed since you first started working in it?

Perhaps its a sign I've been working on the same pathways for too long but there have been dramatic changes over the past 20 years in signal transduction, enabled partly through technological development (tissue-specific gene inactivation, live cell microscopy, and proteomics are a few) but also by the realization that signaling is dynamic and contextual. It's not enough to understand which protein binds to another; you need to know where in the cell, when in the response, and how the cell adapts to the change through feedback systems. I think this is why many promising drugs still fail—we overlook cell-specific and temporally distinct functions associated with a given target.

We're getting better but still have a long way to go in explaining the behavior of these hyper-interactive and inter-dependent pathways. The amazing degrees of stability, consistency of response, and adaptivity inherent in biological systems should play a bigger role in our models to explain how these control circuits work in a reliable manner.

Where do you see this work going in five to ten years?

As we become more sophisticated in experimentation, I think we'll be able to more accurately predict and then mimic the properties of signaling pathways. This should lead to greater chances of success in drug development leading to an effective product without significant side effects. As we understand how these systems talk to each other, we'll be better able to sculpt appropriate treatment regimens, analogous to conformal radiation therapy. Right now, we stick a Hoover Dam in the middle of a surging pathway rather than modulate the tributaries.

I also think that a major benefit of the resequencing projects will be provision of more information about the combinatorial effects of many small differences, leading to interventions tailored to the individual. Since signaling pathways are the conduits of cellular functions, focusing on polymorphisms of the molecules that comprise these systems should provide a practical roadmap for personalized medicine.

Dr. Jim Woodgett
Samuel Lunenfeld Research Institute
Joseph and Wolf Lebovic Health Complex
Mount Sinai Hospital
Toronto, Ontario, Canada

Keywords: signaling pathways, signal transduction, type-2 diabetes, glycogen synthase kinase-3, NF-kappa B, stress-activated protein kinase, SAPK, JNK.