Protein Phosphorylation
Enrique Pimentel in Handbook of Growth Factors, 2017
The protein-tyrosine phosphatases are widely distributed in nature, suggesting a central role in important functions. Two receptor-linked protein-tyrosine phosphatase genes, DLAR and DPTP, were detected in Drosophila by using degenerate oligonucleotide probes containing consensus sequences present in the human genes encoding the HD45 and LAR protein-tyrosine phosphatases.464 The extracellular segments of DLAR and DPTP are composed of multiple immunoglobulin-like domains and FNIII-like domains. The cytoplasmic region of DLAR and DPTP consists of two tandemly repeated tyrosine phosphatase domains. Site-directed mutagenesis indicated that a conserved cysteine residue is essential for protein-tyrosine phosphatase activity.
Marine Natural Products for Human Health Care
Hafiz Ansar Rasul Suleria, Megh R. Goyal in Health Benefits of Secondary Phytocompounds from Plant and Marine Sources, 2021
It was found to inhibit protein tyrosine phosphatase 1B. Another new C22 furano-terpene (dehydrofurodendin) isolated from the sponge (Madagascan Lendenfeldia) was found to be active against HIV-1 RT with an IC50 value of 3.2–5.6 μM [50]. Bioassay-guided fractionation of extracts of the Palauan ascidian (Didemnum guttatum) led to the isolation of a sulfated serinolipid, cyclodidemniserinol trisulfate, as an inhibitor of HIV-1 integrase [191].
Novel imidazopyridine suppresses STAT3 activation by targeting SHP-1
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Jung-Chen Su, Chuan-Hsun Chang, Szu-Hsien Wu, Chung-Wai Shiau
Recent cancer drug discovery has focused on molecular target therapy to reduce nonspecific cytotoxicity in patients. Targeting oncogenes or activating tumour suppressor genes with small molecules is a new approach for cancer treatment. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that plays a central role in tumour cell proliferation, survival, invasion, and immunosuppression1. The STAT3 pathway is activated by several receptors, including those for the interleukin-6 (IL-6) family cytokines2, G-protein-coupled receptors (GPCRs)3,4, and Toll-like receptors (TLRs)5. Once the signal is activated, STAT3 is phosphorylated at the tyrosine 705 residue, resulting in automatic dimerization in the cytosol. The dimeric STAT3 translocates from the cytosol to the nucleus for the transcription of its target genes, such as Mcl-1, Bcl-xl, and VEGF-A6–8 and further regulates cell proliferation, apoptosis, and migration. This phosphorylation activation of STAT3 is negatively regulated by protein tyrosine phosphatases, such as SHP-1, SHP-2, and PTP1B by targeting the phosphor group at tyrosine 7059,10. Therefore, the enhancement of protein tyrosine phosphatases is another approach for target therapy.
Design and synthesis of tricyclic terpenoid derivatives as novel PTP1B inhibitors with improved pharmacological property and in vivo antihyperglycaemic efficacy
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Lingling Yang, Feng Chen, Cheng Gao, Jiabao Chen, Junyan Li, Siyan Liu, Yuanyuan Zhang, Zhouyu Wang, Shan Qian
Protein tyrosine phosphatase 1B (PTP1B) dephosphosphorylates the tyrosine-phosphorylated insulin receptor (IR) and the downstream insulin receptor substrate (IRS) to down regulate insulin transduction10–15. PTP1B inhibitors could potentially improve insulin sensitivity and normalise glucose levels and therefore could be a promising therapeutic strategy in the T2D patients. Recent studies also identified the involvement of intra-islet PTP1B in the regulation of insulin release and reinforce the potential of PTP1B inhibitors for the treatment of beta-cell secretory failure in the pathogenesis of T2D16,17. Besides, PTP1B-mediated dephosphorylation has been implicated in the development of diabetes18, cancer19, hepatic fibrosis20, bacterial infection21, rheumatoid arthritis22 and hypertension23. Many PTP1B inhibitors have been reported, but the discovery of PTP1B inhibitors with superior cell permeability and in vivo potency is difficult and so far there is no PTP1B inhibitors entered III phase clinical trial18,24.
PTPN22: structure, function, and developments in inhibitor discovery with applications for immunotherapy
Published in Expert Opinion on Drug Discovery, 2022
Brenson A. Jassim, Jianping Lin, Zhong-Yin Zhang
Protein tyrosine phosphorylation status regulates the initiation, propagation, and termination of cellular signaling cascades. Protein-tyrosine phosphatases (PTPs), along with the opposing action of protein tyrosine kinases (PTKs), control cellular levels of tyrosine phosphorylation [1-3]. Accordingly, PTPs play an integral role in cellular processes such as growth, differentiation, apoptosis, and metabolism [1–3]. Aberrant PTP activity is associated with numerous human pathologies, including cancer, diabetes, autoimmune disorders and developmental disorders [4–8]. Despite their immense potential as therapeutic targets, PTPs remain a largely untapped drug discovery resource due to innate difficulties in PTP drug discovery (highly conserved and positively charged active sites) and a limited understanding of PTP biology [7,8]. Consisting of 107 members, the PTP superfamily is grouped into four classes [2,9]. PTPN22 (also known as LYP in humans or PEP in mice), the subject of this review, is a classical non-receptor PTP within the proline-rich subclass within class I. PTPN22 is expressed predominantly in immune cells and is a key negative regulator of T-cell receptor (TCR) signal transduction [10]. Notably, a PTPN22 single nucleotide polymorphism (C1858T) causing a missense R620W mutation within a poly-proline motif is implicated in the development of numerous autoimmune disorders [10]. Herein, we succinctly discuss basic elements of PTPN22’s structure, function, and prevalence in autoimmunity and provide in-depth discussion on PTPN22 inhibitor discovery and application to immunotherapy, along with our expert opinion and current state and prospects of the field.
Related Knowledge Centers
- Cell Growth
- Enzyme
- Phosphate
- Signal Transduction
- Phosphorylation
- Tyrosine
- Cell Cycle
- Post-Translational Modification
- Regulation of Gene Expression
- Mapk/Erk Pathway