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Review
. 2022 Jun 4;7(1):177.
doi: 10.1038/s41392-022-01038-3.

Targeting protein phosphatases for the treatment of inflammation-related diseases: From signaling to therapy

Jie Pan #  1 , Lisha Zhou #  1 , Chenyang Zhang  1 , Qiang Xu  1   2 , Yang Sun  3   4
Affiliations
Review

Targeting protein phosphatases for the treatment of inflammation-related diseases: From signaling to therapy

Jie Pan et al. Signal Transduct Target Ther. .

Abstract

Inflammation is the common pathological basis of autoimmune diseases, metabolic diseases, malignant tumors, and other major chronic diseases. Inflammation plays an important role in tissue homeostasis. On one hand, inflammation can sense changes in the tissue environment, induce imbalance of tissue homeostasis, and cause tissue damage. On the other hand, inflammation can also initiate tissue damage repair and maintain normal tissue function by resolving injury and restoring homeostasis. These opposing functions emphasize the significance of accurate regulation of inflammatory homeostasis to ameliorate inflammation-related diseases. Potential mechanisms involve protein phosphorylation modifications by kinases and phosphatases, which have a crucial role in inflammatory homeostasis. The mechanisms by which many kinases resolve inflammation have been well reviewed, whereas a systematic summary of the functions of protein phosphatases in regulating inflammatory homeostasis is lacking. The molecular knowledge of protein phosphatases, and especially the unique biochemical traits of each family member, will be of critical importance for developing drugs that target phosphatases. Here, we provide a comprehensive summary of the structure, the "double-edged sword" function, and the extensive signaling pathways of all protein phosphatases in inflammation-related diseases, as well as their potential inhibitors or activators that can be used in therapeutic interventions in preclinical or clinical trials. We provide an integrated perspective on the current understanding of all the protein phosphatases associated with inflammation-related diseases, with the aim of facilitating the development of drugs that target protein phosphatases for the treatment of inflammation-related diseases.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
A growing tyrosine phosphatase family. Tyr phosphatases are classified based on their nucleophilic catalytic residue (Cys, Asp, or His). The representative schematic depiction and domain composition of the members in each group is shown. Cys-based PTPs contain the signature motif CxxxxxR with 3 classes and 6 subclasses. SAC phosphoinositide phosphatases and PTP-like phytases (PTPLPs) (PALD1/paladin), sharing the PTP fold, have been included in the class I Cys-based group as subclasses III and IV. INPP4 phosphatases (subclass V) and TMEM55 phosphatases have been included in the class I Cys-based group as subclasses V and VI. SSU72 has been included here as part of this class II category of PTPs. Class III phosphatases remain as previously classified. Non-Cys based Tyr phosphatases include the eyes absent (EYA) phosphatases recognized as Asp-based phosphatases. For His-based phosphatases, the ubiquitin-associated (UBA) and Src homology 3 (SH3) domain-containing protein (UBASH3) PGM phosphatases and the acid phosphatases (ACPs) have been incorporated into the extended PTPomes. PTP protein tyrosine phosphatase domain, DSP dual-specificity phosphatase domain, SAC Sac phosphatase domain, AR arsenate reductase, Rhodanese rhodanese phosphatase domain, HAD-ED HAD EYA domain, PGM-HP PGM-like HP domain, Acid HP His acid phosphatase domain, Rhod-like rhodanese-like domain, SH2 Src homology 2 domain, SH3 Src homology 3 domain, FN fibronectin type 3 domain, NHR2 Nervy homology 2 domain, FERM FERM (4.1/ezrin/radixin/moesin) domain, PDZ PDZ (PSD-95/Dlg/ZO-1) domain, UBA ubiquitin-associated domain, Thrp Thr phosphatase region; 5-Phosphatase, 5-phosphoinositide phosphatase domain, C2 domain C2 (C2A-Copine) lipid-binding domain, Pro proline-rich, Gly glycosylated
Fig. 2
Fig. 2
Timeline of the historical milestone for the discovery of protein phosphatases and their crucial inhibitors. SHP099 and TNO155 are SHP2 allosteric inhibitors. ISIS-113715 and MSI-1436 are PTP1B inhibitors. LB-100 is a PP2A inhibitor. PRL3-zumab is a monoclonal antibody of PRL3. The discovery of all the protein phosphatases take a long time and we show the time point for the first identified or cloned of all the protein phosphatases involved in the inflammation-related diseases (PP2A, DUSP1, CD45, PTP1B, PTPN2, PP1, SHP1, SHP2, DUSP2, PP4, PRL-1, PTPN14, DUSP5, DUSP6, PP6, PP2C, PRL-2/3, PTPN22, DUSP10, DUSP14, DUSP22, and DUSP26) and the generation and development of their inhibitors in clinical trials (PRL3-zumb, LB-100242, ISIS113715, MSI-1436, and TNO155.) SHP099 is the first allosteric inhibitor of SHP2 found by Novartis in 2016, which is a breakthrough in the study of allosteric inhibitor in the field of designing compound targeting protein phosphatases
Fig. 3
Fig. 3
The PSP family and the regulated signaling pathways of PP2A in systemic lupus erythematosus (SLE), Alzheimer’s disease (AD), and Parkinson’s disease (PD). a Representative holoenzymes of 3 PSP families. The PPP family contains 7 subfamilies: PP1, PP2A, PP3, PP4, PP5, PP6, and PP7. The catalytic subunits are conserved. PP5 and PP7 work in monomeric enzyme form, while others work in holoenzyme form with the help of catalytic subunits, regulatory subunits, and/or scaffold subunits. The PPM family contains PP2C and PDP. PP2C works in monomeric enzyme form, and PDP works as heterodimer that consists of a regulatory and a catalytic subunit. FCP/SCPs have a conserved structural core of the FCPH domain. b The role of PP2A and its subunits in regulating immune cell differentiation and activation through major signaling pathways in SLE. The aberrant expression of different subunits of PP2A in SLE results in the activation of CD3 T cells, differentiation of Th1 and Th17 cells, and inhibition of Tregs. c The effects of PP2A on the accumulation of Tau, α-syn, and Aβ protein in AD and PD. In neurodegenerative conditions, nuclear pores start to leak, and SET is translocated to the cytoplasm. It then freely diffuses between the nucleus and cytoplasm, but phosphorylation of SET by CKII (casein kinase II) causes its retention in the cytoplasm. Together with an increased activity of GSK3β in the cytoplasm, the consequence is an increased tau phosphorylation, as indicated. PPP phosphoprotein phosphatases, PDP pyruvate dehydrogenase phosphatase, FCP TFIIF-associating component of RNA polymerase II CTD phosphatase, SCP small CTD phosphatase, APP amyloid-β precursor protein. TPR domain the tetratricopeptide repeat domain, FCPH domain FCP-homology domain, CAM-binding motif calmodulin binding motif, IQ motif calmodulin binding motif in PP7, CNB-binding motif calcineurin B binding motif, AI motif autoinhibitory motif, BRCT domain BRCA1 C-terminal domain like domain
Fig. 4
Fig. 4
Immune response and the strategy of targeting phosphatases in inflammatory diseases. The immune response is a multiple process, and the detailed events differ over time. a At the onset of inflammation, innate immune cells are recruited to the injury or infection site within minutes and phagocytize bacteria. Subsequently, the adaptive immune cells infiltrate the site and secrete soluble cytokines, chemokines, or other cytotoxic proteins to activate T-cell killing functions and further scavenge debris. If the previous immune response succeeds in eliminating the infection, inflammation will terminate. If it fails, the proinflammatory immune response will continue for days, months, or even years and lead to chronic inflammation diseases. b Targeting phosphatases will help to advance the process of the inflammation resolution by modulating the function of immune cells, including but not limited to T cells, macrophages, neutrophils, and NK cells. The net result is restoration and maintenance of tissue homeostasis
Fig. 5
Fig. 5
The structure of SHP2 and its function-dependent or independent of phosphatase activity. a–d A schematic diagram of the activation state of SHP2. a The core structure of SHP2. SHP2 consists of two SH2 domains at the N-terminal (N-SH2 and C-SH2), one PTP catalytic domain, and two phosphorylated tyrosine residues at the C-terminal. b, c, d When stimulated with extracellular signals, SHP2 either converts from an autoinhibited state to an activated state upon the binding of phosphoproteins to its SH2 domain or it is autoactivated through phosphorylation at its Tyr site. e–h Four representative phosphatase-dependent functions of SHP2. e SHP2 is translocated into mitochondria, dephosphorylated the Tyr315 site of parkin and further activated by mediated mitophagy. f In acute colitis conditions, SHP2 is moved into the matrix of mitochondria to dephosphorylate ANT1 to maintain mitochondria homeostasis and inhibit inflammation responses. g In osteoarthritis, SHP2 dephosphorylates DOK1, which promotes UPP1-mediated uridine inhibition. h SHP2 dephosphorylates TLR7 and subsequently promotes TLR7 ubiquitination, which activates NF-κB. i–l Phosphatase-independent function of SHP2. i Phosphorylated SHP2 blocks the recruitment of STAT1 to IFN-γR during IFN-γ signaling, STAT1 homodimerization, and nuclear translocation. j EphA2b phosphorylates SHP2 and subsequently increases the binding of growth factor receptor-bound protein 2 (Grb2), which activates ERK signaling. k The C-terminal domain of SHP2 directly binds to the kinase domain of TBK1 to inhibit TBK1-mediated type I IFN signaling pathway. l SHP2 promotes the degradation of fatty acid synthase (FASN) by recruiting the binding of COP1, an E3 ligase
Fig. 6
Fig. 6
The regulating mechanisms of SHP2 in various inflammatory diseases. SHP2 plays a key role in the diverse inflammatory processes illustrated in the figure. SHP2 acts in many cellular signaling pathways in different cell types in inflammatory tissues. In neuroinflammation, SHP2 functions in neuron cells through involvements in the DIR/ERK, JAK/STAT3 and PINK/Parkin signaling pathways to regulate Aβ, tau, and LRKK2 accumulation, and inflammatory cytokine levels. In liver inflammation, SHP2 KO in liver resident macrophages or hepatocytes decreases liver inflammation by inhibiting IL-1β and IL-18 secretion and ROS production. In bone-related inflammatory disease, the different roles of SHP2 in T cells, osteoblasts, chondrocytes, and fibroblasts lead to bone inflammations, such as rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis. In diabetes, abnormal expression of SHP2 in macrophages leads to insulin resistance and metaflammation and further attacks on pancreatic β cells. SHP2 in T cells interacts with PD-1 involved in T1DM. SHP2 also mediates RAS/ERK activation and insulin receptor endocytosis that lead to insulin resistance. In inflammatory intestinal diseases, SHP2 interacts with CagA, activates the RAS/RAF/ERK signaling pathway, and inhibits STAT1 in epithelial cells. SHP2 in macrophages also regulates IL-10 and proinflammatory cytokine secretion in the intestine, thereby affecting nearby club cells and goblet cells. In inflammatory lung diseases, SHP2 in lung epithelial cells, macrophages, neutrophils, and fibroblasts participates in lung inflammation by regulating the epithelial repair process, M2 polarization, neutrophil infiltration into lung tissue, and IFN-γ production. In skin inflammation, SHP2 activates fibroblasts, macrophage-mediated inflammation, T cells s and NETs formation that are responsible for skin inflammation. The figure is generated from BioRender.(https://app.biorender.com)
Fig. 7
Fig. 7
The process and spatial regulation of the inflammation response by SHP2. In the left panel, SHP2 responds quickly and translocates into the mitochondria to interact with ANT1 which inhibits the decrease in mitochondrial membrane potential and mtROS production at the inflammation onset. The early function of SHP2 in acute inflammation prevents the activation of NLRP3 and cytokine release. With the progression of inflammation, SHP2 promotes the TLR7/Endosome/NF-κB-mediated inflammation of psoriasis. Targeting SHP2 with SHP099 could relieve the progression of psoriasis. In the right panel, SHP2 is essential for the gene expression of chondrocytes of the growth plate. Decreased expression of SHP2 in growth plate chondrocytes results in overexpression of BMP6 and facilitates ankylosing spondylitis-like symptoms, while interruption with sonidegib prevents these symptoms. In the chondrocytes of the joint surface, an increased SHP2 expression disrupts the anabolic/catabolic balance and induces osteoarthritis by phosphorylation of its target protein DOK1 at Tyr397, which is associated with UPP1-uridine production. Targeting SHP2 with SHP099 may be a therapeutic strategy for osteoarthritis
Fig. 8
Fig. 8
The regulated signaling pathways of PTP1B in inflammatory diseases. The role of PTP1B in insulin signaling, leptin signaling, and LPS-TLR-mediated inflammatory signaling in diabetes, obesity, and other inflammatory diseases. PTP1B inhibits the phosphorylation of the insulin receptor and insulin receptor substrate and their downstream PI3K/AKT/GLUT4 signaling, thereby preventing the translocation of GLUT4 to the membrane to transport glucose. PTP1B also inhibits JAK2 phosphorylation and attenuates the leptin JAK2/STAT signaling pathway to affect metabolic energy homeostasis. The CREB/KMT5A complex regulates PTP1B to modulate high glucose-induced endothelial inflammatory factor levels in diabetic nephropathy. PTP1B also acts as a negative regulator of TLR signaling via the suppression of both MyD88- and TRIF-dependent production of proinflammatory cytokines in macrophages stimulated by LPS
Fig. 9
Fig. 9
Modes of action of phosphatase inhibitors and activators. a–d The four known types of SHP2 inhibitors have diverse mechanisms that target the catalytic pocket of SHP2, that target the allosteric site of SHP2, that directly degrade the SHP2 protein, or that block the interaction between SHP2 and its substrates. e–h The inhibitor or activators of PP2A, including e a PP2A catalytic inhibitor undergoing clinical trials; f inhibitor of its endogenous inhibitory protein; g direct activator of PP2A; h post-translational modification of PP2A (e.g., methylation and phosphorylation). i Noncompetitive inhibitors of PTP1B bind to a site consisting of the last 20 residues of the catalytic domain. j The antisense oligonucleotide inhibitor of PTP1B messenger RNA reduces the translation of PTP1B protein. k, l JMS-053 and BCI are allosteric inhibitors of PRL3 and DUSP1/6, respectively
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