[Frontiers in Bioscience 3, d961-972, September 1, 1998]
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PHYSIOLOGIC IMPORTANCE OF PROTEIN PHOSPHATASE INHIBITORS

Carey J. Oliver and Shirish Shenolikar

Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710

Received 8/14/98 Accepted 8/20/98

4. PHOSPHATASE INHIBITORS AND HUMAN DISEASE

The physiological relevance for phosphatase inhibitors can often be inferred from their involvement in the pathogenesis of disease. Because of its role in dopaminergic pathways in the brain, DARPP-32 has been implicated in Parkinsonís disease (75). A decrease in dopamine signaling, a hallmark of Parkinsonís, may at least in part be mediated by changes in DARPP-32 activity. Indeed, preliminary studies show that loss of DARPP-32 function in mice elicits locomotor defects similar to Parkinsonís.

There appears to be a strong link between PP2A inhibitors and cancer. I1PP2A is highly expressed in some cancer cells (Z. Damuni, personal communication). In many acute undifferentiated leukemias, a chromosomal translocation on chromosome 9 results in the fusion of SETa (I2PP2A) to the C-terminus of NUP214, a nuclear porin. NUP214 is normally localized to the cytoplasmic side of the nucleus. In contrast, the fusion protein is localized to the interior of the nucleus (76, 77, 78). Moreover, the I2PP2A-NUP214 fusion protein is a more potent PP2A inhibitor than I2PP2A (Z. Damuni, personal communication), suggesting that the more effective inhibition of nuclear PP2A accounts for unregulated growth of leukemic cells.

Deregulation of protein phosphatases has also been implicated in insulin resistance, associated with diabetes mellitus and other metabolic disorders. To what extent the failure of hormones to control protein phosphatase activity in this setting is due to errors in the function of endogenous inhibitors is not certain. Future studies that define the physiological role of protein phosphatases and their regulators should provide new insights into the molecular basis for insulin resistance and other human disorders.

It has long been known that protein serine/threonine phosphatases are the targets for over 50 environmental toxins. While these have been useful tools for studying the phosphatases, they also reveal the essential nature of protein serine/threonine phosphatases to cell physiology. Many of these toxins are also tumor promotors, suggesting the importance of serine/threonine phosphatase inhibition to unregulated cell growth. Additional evidence for this idea comes from the fact that several viral proteins have also been identified which target the inhibition of protein phosphatases to help take control of the cell. Perhaps the best examples of this is the polyoma middle T and SV40 small T antigen which selectively inhibit PP2A. More recently, a viral protein, A238L, from the african swine fever virus has been found to inhibit PP2B (79). The existence of toxins and viral proteins that target serine/thrreonine phosphatases reveals the importance of reversible regulation of endogenous phosphatase inhibitors for proper functioning of phosphatases in cells and suggests the possibility of the involvement of disregulation of inhibitors in the pathogenesis of cancers.