PTP1B: A simple enzyme for a complex world

Abstract

Our understanding of the fundamental regulatory roles that tyrosine phosphatases play within cells has advanced significantly in the last two decades. Out-dated ideas that tyrosine phosphatases acts solely as the "off" switch counterbalancing the action of tyrosine kinases has proved to be flawed. PTP1B is the most characterized of all the tyrosine phosphatases and it acts as a critical negative and positive regulator of numerous signaling cascades. PTP1B's direct regulation of the insulin and the leptin receptors makes it an ideal therapeutic target for type II diabetes and obesity. Moreover, the last decade has also seen several reports establishing PTP1B as key player in cancer serving as both tumor suppressor and tumor promoter depending on the cellular context. Despite many key advances in these fields one largely ignored area is what role PTP1B may play in the modulation of immune signaling. The important recognition that PTP1B is a major negative regulator of Janus kinase - signal transducer and activator of transcription (JAK-STAT) signaling throughout evolution places it as a key link between metabolic diseases and inflammation, as well as a unique regulator between immune response and cancer. This review looks at the emergence of PTP1B through evolution, and then explore at the cell and systemic levels how it is controlled physiologically. The second half of the review will focus on the role(s) PTP1B can play in disease and in particular its involvement in metabolic syndromes and cancer. Finally we will briefly examine several novel directions in the development of PTP1B pharmacological inhibitors.

Novel Non-carboxylate Benzoylsulfonamide-Based Protein Tyrosine Phosphatase 1B Inhibitors with Non-competitive Actions

“…2,4) Inhibitors with two phosphonate or carboxyl substituents exhibit potent PTP1B inhibitory activity, but have low membrane permeability, resulting in poor bioavailability.…”

“…1,2) Thus, PTPs as well as PTKs play important physiological roles and are involved in the pathogeneses of diseases such as diabetes, obesity, autoimmune disorders, cancer, and neurological disorders. [1][2][3] Among PTPs, PTP1B has been shown to negatively regulate insulin signals through the de-phosphorylation of insulin receptors and insulin receptor substrate (IRS), and the leptin signal by the de-phosphorylation of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3). 2,4) PTP1B knockout mice show obesity resistance and insulin hypersensitivity.…”

“…6) Furthermore, PTP1B has been implicated in tumorigenesis, podocyte injury, endothelial dysfunction, and retinal light damage. 1,2,[7][8][9] Based on this background, PTP1B has been attracting attention as a potential therapeutic target and a large number of PTP1B inhibitors have been reported as candidates for anti-diabetic and anti-obesity drugs. 1,[10][11][12] Classically, some types of vanadates have been shown to inhibit PTP1B and exert insulinomimetic actions.…”

“…These inhibitors may be effective against not only diabetes and obesity, but also cancer, neuroinflammation, and retinal and renal failure. 1,2,[7][8][9] Reported allosteric inhibitors consist of two or more aromatic rings connected via acyl, ether, or alkyl linkers, and exhibit relatively weak activity. 11) In the present study, we synthesized a series of benzoylsulfonamide derivatives with a linker and aromatic ring.…”

“…[1][2][3] Among PTPs, PTP1B has been shown to negatively regulate insulin signals through the de-phosphorylation of insulin receptors and insulin receptor substrate (IRS), and the leptin signal by the de-phosphorylation of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3). 2,4) PTP1B knockout mice show obesity resistance and insulin hypersensitivity. 5) A PTP1B antisense oligonucleotide normalizes glucose levels and improves insulin resistance in diabetic mice.…”