Vanadate inhibits PTP1B

Found another Interesting connection - between Vanadium and PTP1B enzyme.

PTP1B and obesity

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of the leptin and insulin signaling pathways.

The important roles of PTP1B related to obesity and diabetes were confirmed by a deletion of PTP1B gene in mice.

Mice with the whole body deletion of PTP1B were protected against the development of obesity and diabetes. (R3)

Another study came to the same conclusion:

Our data indicate that hepatic-PTP1B inhibition protects against HFD-induced endothelial dysfunction, underscoring the potential of peripheral PTP1B inhibitors in reduction of obesity-associated cardiovascular risk in addition to its anti-diabetic effects.

Psychiatric disorders

In addition to recognised roles in obesity and insulin sensitivity, PTP1B has a role in psychiatric disorders:

PTP1B has attracted attention in the field of neuroscience, since its activation in brain cells can lead to schizophrenia-like behaviour deficits, anxiety-like effects, neurodegeneration, neuroinflammation and depression.

Conversely, PTP1B inhibition has been shown to prevent microglial activation, thus exerting a potent anti-inflammatory effect and has also shown potential to increase the cognitive process through the stimulation of hippocampal insulin, leptin and BDNF/TrkB receptors.

Notwithstanding, most research on the clinical efficacy of targeting PTP1B has been developed in the field of obesity and type 2 diabetes mellitus (TD2M). (R1)

Inflammation activates PTP1B

Ischemic brain injury causes neuronal death and inflammation. Inflammation activates protein-tyrosine phosphatase 1B (PTP1B). (R5)

Overactive PTP1B contributes to anxiety-like behaviours

Taken together, our study identifies neuronal PTP1B as a key component that hinders sensory and motor functional recovery and also contributes to the development of anxiety-like and depression-like behaviors after stroke. Thus, PTP1B may represent a novel therapeutic target to improve stroke recovery. (R5)

Vanadate inhibits PTP1B

Our results show that vanadate is a competitive inhibitor for the protein-tyrosine phosphatase PTP1B. (R2)

Hydrogen Sulfide inhibits PTP1B

we report that PTP1B, the founding member of this enzyme family, was reversibly inactivated by H2S, in vitro and in vivo, via sulfhydration of the active site Cys residue. Unlike oxidized PTP1B, the sulfhydrated enzyme was preferentially reduced by thioredoxin in vitro, compared to glutathione or dithiothreitol. Sulfhydration of the active site Cys in PTP1B in cells required the presence of cystathionine-γ-lyase (CSE), a critical enzyme in H2S production, and resulted in inhibition of phosphatase activity (R7)

Calcium inhibits PTP1B indirectly and helps to maintain positive feedback loop

Tyrosine phosphatase PTP1B interacts with TRPV6 in vivo and plays a role in TRPV6-mediated calcium influx in HEK293 cells, Cell Signal 17 (2005) 951-960].

Since Ca2+ does not directly inhibit PTP1B, we assumed an intermediate signal, which links the rise in cytosolic Ca2+ concentration and PTP1B inhibition.

We now show that Ca2+ influx is followed by generation of reactive oxygen species (ROS) and that it is reduced in cells preincubated with catalase. Furthermore, Ca2+-dependent inhibition of PTP1B can be abolished in the presence of catalase.

H2O2 (100 microM) directly added to cells inhibits PTP1B and leads to increase in Ca2+ influx after store depletion. PP1, an inhibitor of the Src family tyrosine kinases, prevents H2O2-induced Ca2+ influx.

Our results show that ROS act as fine tuning modulators of Ca2+ entry. We assume that the Ca2+ influx channel or a protein involved in its regulation remains tyrosine phosphorylated as a consequence of PTP1B inhibition by ROS. This leads to maintained Ca2+ influx in the manner of a positive feedback loop. (R8)