Thirty Years of Protein Tyrosine Phosphatases – From Housekeeping Enzymes to Therapeutic Targets

Abstract

Thirty years ago, while working with Eddy Fischer at the UW in Seattle, I succeeded in purifying a protein tyrosine phosphatase (PTP) to homogeneity for the first time. Together with Harry Charbonneau and Ken Walsh, we sequenced the protein, PTP1B, and demonstrated homology with CD45, going on to show that CD45 possessed intrinsic PTP activity. This was important because CD45 is a receptor‐like protein – this observation illustrated the existence of receptor‐like PTPs with the potential to regulate signaling through ligand‐modulated protein tyrosine de‐phosphorylation. Now, we know that PTP1B was the prototype for a large family of such enzymes, comprising ~100 members in humans. Although initially viewed merely as constitutively active housekeeping enzymes, it has now become apparent that the protein phosphatases are critical, specific regulators of signaling in their own right and serve an essential function, in a coordinated manner with the kinases, to determine the response to a physiological stimulus. My lab takes a multidisciplinary approach to characterizing the structure, regulation and function of members of the PTP family of enzymes, with the goal of defining their role in the control of normal and pathophysiological cell function and using them as the basis for identifying novel therapeutic targets and strategies for treatment of major human diseases.As functional studies have established links to disease, the PTPs have been garnering attention as potential therapeutic targets; however, they remain a largely untapped resource for drug development. As a validated target for diabetes and obesity, as well as HER2‐positive cancer, PTP1B has been the subject of extensive drug discovery efforts. Nevertheless, in following established approaches to develop small molecule drugs that bind to the active site of an enzyme, industry has found PTPs to be challenging therapeutic targets. Although it was possible to generate potent, specific and reversible inhibitors of PTP1B, such molecules were highly charged, due to the chemistry underlying PTP‐mediated catalysis, and thus of limited drug development potential. This led industry to conclude that the members of the PTP family are “undruggable”. Consequently, new approaches are required to exploit this important target effectively and to reinvigorate drug discovery efforts.In this presentation, I will discuss how a detailed understanding of the structure, regulation and function of PTP1B, generated in an academic setting, is revealing new approaches to the development of small molecule drug candidates. This is also being extended to other members of the PTP family. Continued progress in this area is now leading to the establishment of novel PTP‐based therapeutics for the treatment of major human diseases.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.