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Journal of Medicinal Chemistry Jul 2021Among numerous posttranslational regulation patterns, phosphorylation is reversibly controlled by the balance of kinases and phosphatases. The major form of cellular... (Review)
Review
Among numerous posttranslational regulation patterns, phosphorylation is reversibly controlled by the balance of kinases and phosphatases. The major form of cellular signaling involves the reversible phosphorylation of proteins on tyrosine, serine, or threonine residues. However, altered phosphorylation levels are found in diverse diseases, including cancer, making kinases and phosphatases ideal drug targets. In contrast to the success of prosperous kinase inhibitors, design of small molecules targeting phosphatase is struggling due to past bias and difficulty. This is especially true for serine/threonine phosphatases, one of the largest phosphatase families. From this perspective, we aim to provide insights into serine/threonine phosphatases and the small molecules targeting these proteins for drug development, especially in cancer. Through highlighting the modulation strategies, we aim to provide basic principles for the design of small molecules and future perspectives for the application of drugs targeting serine/threonine phosphatases.
Topics: Animals; Antineoplastic Agents; Enzyme Inhibitors; Humans; Molecular Structure; Neoplasms; Phosphoprotein Phosphatases; Small Molecule Libraries
PubMed: 34156850
DOI: 10.1021/acs.jmedchem.1c00631 -
Molecules and Cells Sep 2016Almost all eukaryotic proteins are subject to post-translational modifications during mitosis and cell cycle, and in particular, reversible phosphorylation being a key... (Review)
Review
Almost all eukaryotic proteins are subject to post-translational modifications during mitosis and cell cycle, and in particular, reversible phosphorylation being a key event. The recent use of high-throughput experimental analyses has revealed that more than 70% of all eukaryotic proteins are regulated by phosphorylation; however, the mechanism of dephosphorylation, counteracting phosphorylation, is relatively unknown. Recent discoveries have shown that many of the protein phosphatases are involved in the temporal and spatial control of mitotic events, such as mitotic entry, mitotic spindle assembly, chromosome architecture changes and cohesion, and mitotic exit. This implies that certain phosphatases are tightly regulated for timely dephosphorylation of key mitotic phosphoproteins and are essential for control of various mitotic processes. This review describes the physiological and pathological roles of mitotic phosphatases, as well as the versatile role of various protein phosphatases in several mitotic events.
Topics: Animals; Cell Cycle; Humans; Mitosis; Phosphoprotein Phosphatases; Phosphorylation
PubMed: 27669825
DOI: 10.14348/molcells.2016.0214 -
BMC Biology May 2024The innate immune system serves as the first line of host defense. Transforming growth factor-β-activated kinase 1 (TAK1) is a key regulator of innate immunity, cell...
BACKGROUND
The innate immune system serves as the first line of host defense. Transforming growth factor-β-activated kinase 1 (TAK1) is a key regulator of innate immunity, cell survival, and cellular homeostasis. Because of its importance in immunity, several pathogens have evolved to carry TAK1 inhibitors. In response, hosts have evolved to sense TAK1 inhibition and induce robust lytic cell death, PANoptosis, mediated by the RIPK1-PANoptosome. PANoptosis is a unique innate immune inflammatory lytic cell death pathway initiated by an innate immune sensor and driven by caspases and RIPKs. While PANoptosis can be beneficial to clear pathogens, excess activation is linked to pathology. Therefore, understanding the molecular mechanisms regulating TAK1 inhibitor (TAK1i)-induced PANoptosis is central to our understanding of RIPK1 in health and disease.
RESULTS
In this study, by analyzing results from a cell death-based CRISPR screen, we identified protein phosphatase 6 (PP6) holoenzyme components as regulators of TAK1i-induced PANoptosis. Loss of the PP6 enzymatic component, PPP6C, significantly reduced TAK1i-induced PANoptosis. Additionally, the PP6 regulatory subunits PPP6R1, PPP6R2, and PPP6R3 had redundant roles in regulating TAK1i-induced PANoptosis, and their combined depletion was required to block TAK1i-induced cell death. Mechanistically, PPP6C and its regulatory subunits promoted the pro-death S166 auto-phosphorylation of RIPK1 and led to a reduction in the pro-survival S321 phosphorylation.
CONCLUSIONS
Overall, our findings demonstrate a key requirement for the phosphatase PP6 complex in the activation of TAK1i-induced, RIPK1-dependent PANoptosis, suggesting this complex could be therapeutically targeted in inflammatory conditions.
Topics: Receptor-Interacting Protein Serine-Threonine Kinases; Humans; Phosphoprotein Phosphatases; MAP Kinase Kinase Kinases; Necroptosis; Immunity, Innate
PubMed: 38807188
DOI: 10.1186/s12915-024-01901-5 -
Cellular Signalling Sep 2021Protein phosphorylation and dephosphorylation is central to signal transduction in nearly every aspect of cellular function, including cardiovascular regulation and... (Review)
Review
Protein phosphorylation and dephosphorylation is central to signal transduction in nearly every aspect of cellular function, including cardiovascular regulation and diseases. While protein kinases are often regarded as the molecular drivers in cellular signaling with high specificity and tight regulation, dephosphorylation mediated by protein phosphatases is also gaining increasing appreciation as an important part of the signal transduction network essential for the robustness, specificity and homeostasis of cell signaling. Metal dependent protein phosphatases (PPM, also known as protein phosphatases type 2C, PP2C) belong to a highly conserved family of protein phosphatases with unique biochemical and molecular features. Accumulating evidence also indicates important and specific functions of individual PPM isoform in signaling and cellular processes, including proliferation, senescence, apoptosis and metabolism. At the physiological level, abnormal PPM expression and activity have been implicated in major human diseases, including cancer, neurological and cardiovascular disorders. Finally, inhibitors for some of the PPM members have been developed as a potential therapeutic strategy for human diseases. In this review, we will focus on the background information about the biochemical and molecular features of major PPM family members, with emphasis on their demonstrated or potential roles in cardiac pathophysiology. The current challenge and potential directions for future investigations will also be highlighted.
Topics: Humans; Phosphoprotein Phosphatases; Phosphorylation; Protein Phosphatase 2; Protein Phosphatase 2C; Signal Transduction
PubMed: 34091011
DOI: 10.1016/j.cellsig.2021.110061 -
Redox Biology Oct 2019Cellular processes are dictated by the active signaling of proteins relaying messages to regulate cell proliferation, apoptosis, signal transduction and cell... (Review)
Review
Cellular processes are dictated by the active signaling of proteins relaying messages to regulate cell proliferation, apoptosis, signal transduction and cell communications. An intricate web of protein kinases and phosphatases are critical to the proper transmission of signals across such cascades. By governing 30-50% of all protein dephosphorylation in the cell, with prominent substrate proteins being key regulators of signaling cascades, the phosphatase PP2A has emerged as a celebrated player in various developmental and tumorigenic pathways, thereby posing as an attractive target for therapeutic intervention in various pathologies wherein its activity is deregulated. This review is mainly focused on refreshing our understanding of the structural and functional complexity that cocoons the PP2A phosphatase, and its expression in cancers. Additionally, we focus on its physiological regulation as well as into recent advents and strategies that have shown promise in countering the deregulation of the phosphatase through its targeted reactivation. Finally, we dwell upon one of the key regulators of PP2A in cancer cells-cellular redox status-its multifarious nature, and its integration into the reactome of PP2A, highlighting some of the significant impacts that ROS can inflict on the structural modifications and functional aspect of PP2A.
Topics: Animals; Carcinogenesis; Cell Proliferation; Humans; Neoplasms; Oxidation-Reduction; Phosphoprotein Phosphatases; Signal Transduction
PubMed: 30686777
DOI: 10.1016/j.redox.2019.101105 -
Nature Communications Mar 2021Increased adiposity confers risk for systemic insulin resistance and type 2 diabetes (T2D), but mechanisms underlying this pathogenic inter-organ crosstalk are...
Increased adiposity confers risk for systemic insulin resistance and type 2 diabetes (T2D), but mechanisms underlying this pathogenic inter-organ crosstalk are incompletely understood. We find PHLPP2 (PH domain and leucine rich repeat protein phosphatase 2), recently identified as the Akt Ser473 phosphatase, to be increased in adipocytes from obese mice. To identify the functional consequence of increased adipocyte PHLPP2 in obese mice, we generated adipocyte-specific PHLPP2 knockout (A-PHLPP2) mice. A-PHLPP2 mice show normal adiposity and glucose metabolism when fed a normal chow diet, but reduced adiposity and improved whole-body glucose tolerance as compared to Cre- controls with high-fat diet (HFD) feeding. Notably, HFD-fed A-PHLPP2 mice show increased HSL phosphorylation, leading to increased lipolysis in vitro and in vivo. Mobilized adipocyte fatty acids are oxidized, leading to increased peroxisome proliferator-activated receptor alpha (PPARα)-dependent adiponectin secretion, which in turn increases hepatic fatty acid oxidation to ameliorate obesity-induced fatty liver. Consistently, adipose PHLPP2 expression is negatively correlated with serum adiponectin levels in obese humans. Overall, these data implicate an adipocyte PHLPP2-HSL-PPARα signaling axis to regulate systemic glucose and lipid homeostasis, and suggest that excess adipocyte PHLPP2 explains decreased adiponectin secretion and downstream metabolic consequence in obesity.
Topics: Adipocytes; Adiponectin; Adipose Tissue; Adiposity; Animals; Diet, High-Fat; Fatty Acids; Fatty Liver; Gene Expression Regulation; Glucose; Homeostasis; Humans; Insulin Resistance; Lipid Metabolism; Lipolysis; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Obesity; PPAR alpha; Phosphoprotein Phosphatases; Phosphorylation; Signal Transduction; Sterol Esterase
PubMed: 33758172
DOI: 10.1038/s41467-021-22106-2 -
Cellular Signalling Oct 2021PH domain leucine-rich repeat protein phosphatase (PHLPP) is a family of enzymes made up of two isoforms (PHLPP1 and PHLPP2), whose actions modulate intracellular... (Review)
Review
PH domain leucine-rich repeat protein phosphatase (PHLPP) is a family of enzymes made up of two isoforms (PHLPP1 and PHLPP2), whose actions modulate intracellular activity via the dephosphorylation of specific serine/threonine (Ser/Thr) residues on proteins such as Akt. Recent data generated in our lab, supported by findings from others, implicates the divergent roles of PHLPP1 and PHLPP2 in maintaining cellular homeostasis since dysregulation of these enzymes has been linked to various pathological states including cardiovascular disease, diabetes, ischemia/reperfusion injury, musculoskeletal disease, and cancer. Therefore, development of therapies to modulate specific isoforms of PHLPP could prove to be therapeutically beneficial in several diseases especially those targeting the cardiovascular system. This review is intended to provide a comprehensive summary of current literature detailing the role of the PHLPP isoforms in the development and progression of heart disease.
Topics: Humans; Neoplasms; Nuclear Proteins; Phosphoprotein Phosphatases; Protein Isoforms; Proto-Oncogene Proteins c-akt
PubMed: 34320369
DOI: 10.1016/j.cellsig.2021.110097 -
Annual Review of Microbiology 2015The role of protein phosphatases in pathogenic bacteria has been studied extensively over the last two decades. Ser/Thr and Tyr phosphatases are associated with growth... (Review)
Review
The role of protein phosphatases in pathogenic bacteria has been studied extensively over the last two decades. Ser/Thr and Tyr phosphatases are associated with growth and virulence of many bacteria. These phosphatases control kinase-mediated functions and return the proteins to their unmodified state. Biochemical, structural, and functional studies, in addition to extensive genetic characterization, have highlighted the importance of phosphatases in bacteria. However, questions remain regarding the mechanisms driving localization of secretory phosphatases to cellular compartments, identification of receptor phosphatase sensory signals, and a possible role of cofactors and ligands in their functions. This review focuses on the role of Ser/Thr- and Tyr-specific phosphatases present in pathogenic bacteria, with an emphasis on the regulation of basic cellular processes and virulence. Furthermore, we highlight their clinical importance and analyze the development of drugs targeting protein phosphatases.
Topics: Bacteria; Bacterial Physiological Phenomena; Phosphoprotein Phosphatases; Virulence
PubMed: 26359969
DOI: 10.1146/annurev-micro-020415-111342 -
Cell Reports Jan 2022Acute myeloid leukemia (AML) cells rely on phospho-signaling pathways to gain unlimited proliferation potential. Here, we use domain-focused CRISPR screening and...
Acute myeloid leukemia (AML) cells rely on phospho-signaling pathways to gain unlimited proliferation potential. Here, we use domain-focused CRISPR screening and identify the nuclear phosphatase SCP4 as a dependency in AML, yet this enzyme is dispensable in normal hematopoietic progenitor cells. Using CRISPR exon scanning and gene complementation assays, we show that the catalytic function of SCP4 is essential in AML. Through mass spectrometry analysis of affinity-purified complexes, we identify the kinase paralogs STK35 and PDIK1L as binding partners and substrates of the SCP4 phosphatase domain. We show that STK35 and PDIK1L function catalytically and redundantly in the same pathway as SCP4 to maintain AML proliferation and to support amino acid biosynthesis and transport. We provide evidence that SCP4 regulates STK35/PDIK1L through two distinct mechanisms: catalytic removal of inhibitory phosphorylation and by promoting kinase stability. Our findings reveal a phosphatase-kinase signaling complex that supports the pathogenesis of AML.
Topics: Cell Line, Tumor; Cell Proliferation; Humans; Leukemia, Myeloid, Acute; Phosphoprotein Phosphatases; Phosphorylation; Protein Serine-Threonine Kinases; Signal Transduction
PubMed: 35021089
DOI: 10.1016/j.celrep.2021.110233 -
Annual Review of Pharmacology and... Jan 2021Whereas protein kinases have been successfully targeted for a variety of diseases, protein phosphatases remain an underutilized therapeutic target, in part because of... (Review)
Review
Whereas protein kinases have been successfully targeted for a variety of diseases, protein phosphatases remain an underutilized therapeutic target, in part because of incomplete characterization of their effects on signaling networks. The pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP) is a relatively new player in the cell signaling field, and new roles in controlling the balance among cell survival, proliferation, and apoptosis are being increasingly identified. Originally characterized for its tumor-suppressive function in deactivating the prosurvival kinase Akt, PHLPP may have an opposing role in promoting survival, as recent evidence suggests. Additionally, identification of the transcription factor STAT1 as a substrate unveils a role for PHLPP as a critical mediator of transcriptional programs in cancer and the inflammatory response. This review summarizes the current knowledge of PHLPP as both a tumor suppressor and an oncogene and highlights emerging functions in regulating gene expression and the immune system. Understanding the context-dependent functions of PHLPP is essential for appropriate therapeutic intervention.
Topics: Humans; Neoplasms; Nuclear Proteins; Phosphoprotein Phosphatases; Proto-Oncogene Proteins c-akt; Signal Transduction
PubMed: 32997603
DOI: 10.1146/annurev-pharmtox-031820-122108