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JAK-STAT pathway: Testicular development, spermatogenesis and fertility
Published in Rajender Singh, Molecular Signaling in Spermatogenesis and Male Infertility, 2019
For fine-tuning of the pathway, there are positive and negative regulators that exist in the vertebrate and invertebrate systems. Positive regulation involves the ligand molecules (15), and negative regulation involves three basic mechanisms: dephosphorylation by protein tyrosine phosphatase (PTPs), STAT inhibition by protein inhibitors of activated STAT (PIAS) and negative feedback by suppressors of the cytokine signaling (SOCS) (14). As tyrosine phosphorylation is a central event in the pathway and activates the major players such as JAK and STAT, dephosphorylation of these positive regulators will have a negative effect on the pathway. The enzymes that are involved in dephosphorylation are called phosphatases. In mammals, the known tyrosine phosphatases are SHP1 (SH2 domain containing phosphatase), SHP2, protein tyrosine phosphatase B1 (PTPB1) and T-cell protein tyrosine phosphatase (TC-PTPs) (31). PIAS, as the name suggests, are the inhibitors of phosphorylated STAT. They constitute an E3 sumo ligase family and have four members present in mammals: PIAS1, PIASx, PIAS3 and PIASy (32). SOCS proteins suppress the JAK-STAT signaling pathway and generate a negative feedback loop in both mammals and Drosophila (33).
Herbs with Antidepressant Effects
Published in Scott Mendelson, Herbal Treatment of Major Depression, 2019
Glycyrrhiza also has significant antidiabetic and insulin-enhancing effects. Glycyrrhizin significantly improved blood glucose levels and enhanced insulin sensitivity in rats made diabetic with streptozotocin.9 Phenolic phytochemicals extracted from Glycyrrhiza glabra species stimulate PPARγ,10 whereas glycybenzofuran and glisoflavone from Glycyrrhiza uralensis inhibit protein tyrosine phosphatase 1B.11 Protein tyrosine phosphatase 1B is a negative regulator of insulin and the leptin signaling pathway.
Protein Phosphorylation
Published in Enrique Pimentel, 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.
An overview of the molecular and clinical significance of the angiopoietin system in leukemia
Published in Journal of Receptors and Signal Transduction, 2023
Saeed Zaka Khosravi, Samira Molaei Ramshe, Mehdi Allahbakhshian Farsani, Mohammadreza Moonesi, Faroogh Marofi, Majid Farshdousti Hagh
The exact role of Tie-1 in the Ang–Tie system is controversial and is not completely defined. The Tie-2 activation by Ang-1 contributes to Tie-2/Tie-1 heterodimer dissociation, Tie-2 clustering, stimulation of downstream signaling pathway, and Tie-1 phosphorylation in Tie-2-dependent fashion [31,87,90]. Milner et al. stated that Tie-1 could not alter anti-apoptotic or anti-permeability facets of Ang-1 on endothelial cells. They hypothesized that Tie-1 might affect other functional aspects of Ang-1 on endothelial cells [91]. On the other hand, further studies have not found a specific role for Tie-1 in the Ang–Tie-2 signaling system. Some studies recommended Tie-1 as a contributor for the agonistic roles of the Ang-1 and Ang-2 [30,92,93], but conversely, others showed it to be a negative regulator of Tie-2 activation [87,94]. Also, the context-dependent regulatory role of Tie-1 upon Tie-2 signaling is revealed [90]. A recent study shows that inhibition of vascular endothelial protein tyrosine phosphatase (VE-PTP) as an Ang-2 regulator along with Tie-1 and Tie-2 shedding inhibition enhances Tie-2 activation [95]. It seems that increased Tie-1 expression is correlated with CLL cell proliferation [42] and shorter survival in CML patients [44]. Tie-1 increased level in AML patients has shown no effect on the outcome of patients (Table 1) [43]. Also, one study has demonstrated Tie-1 expression in AML but not in ALL patients [96]. Taken together, more studies are needed in defining the exact role of Tie-1 in the Ang–Tie system and angiogenesis.
Evaluation of sodium orthovanadate as a radioprotective agent under total-body irradiation and partial-body irradiation conditions in mice
Published in International Journal of Radiation Biology, 2021
Yuichi Nishiyama, Akinori Morita, Bing Wang, Takuma Sakai, Dwi Ramadhani, Hidetoshi Satoh, Kaoru Tanaka, Megumi Sasatani, Shintaro Ochi, Masahide Tominaga, Hitoshi Ikushima, Junji Ueno, Mitsuru Nenoi, Shin Aoki
Vanadate is also known to inactivate protein tyrosine phosphatases (PTPase) (Gordon 1991) and adenosine triphosphatases (ATPase) (Aureliano and Crans 2009). Our previous study compared antiapoptotic effect of vanadate in irradiated MOLT-4 cells with several PTPase inhibitors, and the results suggested that the suppression of radiation-induced MOLT-4 apoptosis of vanadate is not associated with its PTPase-inhibiting effect (Morita et al. 2006). Therefore, the inhibiting effect of vanadate may not a contributing factor to the lethalities of TBI and PBI. Sodium-potassium ATPase (Na+/K+-ATPase), transmembrane protein that is effectively inhibited by vanadate (Aureliano and Crans 2009; Jiang et al. 2018), plays a central role in water and glucose absorptions in the intestine. Lebrun et al. demonstrated the reduction of Na+/K+-ATPase activity in rats treated with 8 Gy-TBI (Lebrun et al. 1998), and loss of the activity could result in radiation malabsorptive diarrhea (MacNaughton 2000). Since weight gain, stool consistency, and survival rate showed no differences for 60 days between unirradiated mice treated with or without a single injection of 20 mg/kg vanadate (data not shown), the dose was considered to have no effect on physiological condition. Detailed studies are needed to examine the vanadate requirement sufficient to inactivate Na+/K+-ATPase in GI tissue and how the inactivation affect in the development of radiation GI syndrome.
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.