Miklós Bodanszky Award Lecture: Advances in the selective targeting of protein phosphatase‐1 and phosphatase‐2A with peptides

Abstract

Protein phosphatase‐1 and phosphatase‐2A are two ubiquitously expressed enzymes known to catalyze the majority of dephosphorylation reactions on serine and threonine inside cells. They play roles in most cellular processes and are tightly regulated by regulatory subunits in holoenzymes. Their misregulation and malfunction contribute to disease development and progression, such as in cancer, diabetes, viral infections, and neurological as well as heart diseases. Therefore, targeting these phosphatases for therapeutic use would be highly desirable; however, their complex regulation and high conservation of the active site have been major hurdles for selectively targeting them in the past. In the last decade, new approaches have been developed to overcome these hurdles and have strongly revived the field. I will focus here on peptide‐based approaches, which contributed to showing that these phosphatases can be targeted selectively and aided in rethinking the design of selective phosphatase modulators. Finally, I will give a perspective on www.depod.org, the human dephosphorylation database, and how it can aid phosphatase modulator design. © 2017 The Authors. Journal of Peptide Science published by European Peptide Society and John Wiley & Sons Ltd.

Interrogating PP1 Activity in the MAPK Pathway with Optimized PP1‐Disrupting Peptides

“…Protein phosphatase‐1 (PP1) is a Ser/Thr‐specific phosphoprotein phosphatase (PPP) that has central roles in cellular and organismal physiology, and has been implicated in several human diseases associated with deregulated phosphorylation . PP1 holoenzymes each contain a conserved catalytic subunit with an active‐site pocket that is highly similar to that of other PPPs, and one or two regulatory proteins that determine substrate specificity, cellular localization, or activity . A major obstacle to understanding the roles of PP1 in cellular signaling pathways is the lack of tools to selectively modulate PP1 activity without influencing other PPPs .…”

Functions and therapeutic potential of protein phosphatase 1: Insights from mouse genetics

“…Consistent with its numerous substrates, PP1 is a key regulator of several cellular processes, including cell cycle progression, protein synthesis, pre-mRNA splicing and transcription. It is therefore not surprising that PP1 plays a crucial role in human pathologies such as cancer, heart disease, memory loss, type 2 diabetes and viral infections, suggesting a great therapeutic potential for PP1-directed drugs [17,18]. Genetically engineered mouse models have significantly contributed to our understanding of the physiological role of PP1 holoenzymes in health and diseases as they can determine in vivo gene function and identify disease-causing target genes [19,20].…”

Emerging roles of the Protein Phosphatase 1 (PP1) in the context of viral infections

“…The design of selective modulators for PP1’s active site is highly challenging due to its great conservation within the PPP family [ 192 , 193 ]. However, PP1 holoenzymes can be selectively targeted by interference with PP1:RIPPO interactions [ 16 , 194 ]. One effective approach is the design and synthesis of PP1-disrupting peptides that allow the disruption of PP1 holoenzymes’ interactions and the modulation of certain processes [ 195 – 198 ].…”