The Physiological Relevance of Protein Phosphatase 1 and its Interacting Proteins to Health and Disease

Abstract

Protein phosphorylation is a major regulatory mechanism of signal transduction cascades in eukaryotic cells, catalysed by kinases and reversed by protein phosphatases (PPs). Sequencing of entire genomes has revealed that ~3% of all eukaryotic genes encode kinases or PPs. Surprisingly, there appear to be 2-5 times fewer PPs than kinases. Over the past two decades it has become apparent that the diversity of Ser/Thr-specific PPs (STPP) was achieved not only by the evolution of new catalytic subunits, but also by the ability of a single catalytic subunit to interact with multiple interacting proteins. PP1, a STPP, is involved in the control of important cellular mechanisms. Several isoforms of PP1 are known in mammals: PP1α, PP1β and PP1γ. The various isoforms are highly similar, except for the N- and C-termini. The current view is that since PPs possess exquisite specificities in vivo, the key control mechanism must reside in the nature of the PP1 Interacting Protein (PIP) to which they bind. An increasing number of PIPs have been identified that are responsible for regulating the catalytic activity of PPs. Indeed, the diversity of such PIPs explains the need for relatively few catalytic subunit types, and makes them attractive targets for pharmacological intervention. This review will summarize the PIPs identified using the Yeast Two Hybrid methodology and alternative techniques, for instance bioinformatic and proteomic approaches. Further, it compiles 129 PP1-PIP relevant physiological interactions that are well documented in the literature. Finally, the use of PIPs as therapeutic targets will be addressed.

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

“…As illustrated by the low TV score for phosphatases (Suppl Table S3), further validation studies are needed before phosphatase inhibition can be pursued as a therapeutic option. Of note, the identity of the PP1/PP2A regulatory subunits mediating Htt dephosphorylation remains unknown, although their inhibition might be more successful than the development of active site inhibitors, since the active phosphatase subunits are very promiscuous in terms of substrate specificity 115 . Upregulation of Akt activity on the other hand could be achieved through the modulation of the upstream IGF-1 and PI3K signalling pathway 107 .…”

Plasmodium falciparum Inhibitor-3 Homolog Increases Protein Phosphatase Type 1 Activity and Is Essential for Parasitic Survival

“…These regulators mainly include proteins with a degenerate sequence motif ((K/R)X 0 -1 (V/I)p(F/W), known as the RVXF-binding motif to PP1 (9). Biochemical, interaction, and genetic studies clearly indicated that PP1 regulators are as crucial as PP1 itself in the control of cell vitality and survival (10). Hence, the multiple functions of PP1 seem to be organized * This work was supported in part by Inserm, Institut Pasteur de Lille, Université Lille Nord de France, and TGE RMN THC Grant FR-3050, France.…”

Prostate cancer: the need for biomarkers and new therapeutic targets

“…In cancer, imbalances in protein phosphorylation systems appear to be an important pathophysiologic mechanism. Since the activation of several kinases results in stimulation of cell signaling pathways that potentiate cell growth and proliferation, it is not surprising that tumor suppressive functions have been attributed to phosphatases (Fardilha et al, 2010).…”

“…Because of the numerous functions of PPP1 and PPP2 catalytic subunits, the long-term usage of these enzyme inhibitors is associated with nephrotoxicity and hepatotoxicity. For this reason, a more satisfactory option seems to be to target PPP1 interacting proteins (PIPs) instead of protein phosphatases directly, as they are more event, tissue, and subcellular compartment specific (Fardilha et al, 2010). Two targeted PPP1-PIP complexes have already been described: (1) the PPP1-GADD34 complex, which is diminished in cells treated with salubrinal-a small molecule that protects the cell from ERstress-induced apoptosis; and (2) PPP1 and histone deacetylases (HDACs), an example of which is trichostatin A, which disrupt the PPP1-HDAC6 complex in glioblastoma and PCa cells (McConnell and Wadzinski, 2009).…”