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

M.      Fardilha; S.      L.C. Esteves; L.      Korrodi-Gregorio; O.      A.B. da Cruz e Silva; E.      F. da Cruz e Silva

doi:10.2174/092986710793205363

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 ∼37percnt; 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.

Keywords: Protein phosphorylation, signal transduction, regulation, interactome, yeast two hybrid, drug target, cancer, Alzheimer's disease, protein phosphatases, PPs, Ser/Thr-specific PPs, STPP, PP1 Interacting Protein, PIP, Protein kinase, glycogen synthase kinase, Tau protein phosphatase, protein kinase C, Alpha-synuclein, Epithermal Growth Factor Receptors, EGFR, Vascular Endothelial Growth Factor Receptors, VEGFR, Platelet-Derived Growth Factor Receptors, PDGFR, fostriecin, RVxF motif, SILK motif, microcystin-Sepharose chromatography, Cantharidin, Histone deacetylases, HDACs, Prostate-specific membrane antigen, PSM, ASON