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Tyrosine Phosphatases as New Treatment Targets in Acute Myeloid Leukemia
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
I. Hubeek, K. Hoorweg, J. Cloos, Gertjan J. L. Kaspers
The human genome codes for at least 107 PTP genes, together referred as the PTPome (Table 1) (13). Of the 107 PTP genes, 11 are catalytically inactive, 2 dephosphorylate mRNA, and 13 dephosphorylate inositol phospholipids. Thus, 81 PTPs are active protein phosphatases with the ability to dephosphorylate phosphotyrosine (pTyr). The PTP superfamily is characterized by the presence of an approximately 250 amino acids long, absolutely conserved signature motif (H/V)C(X)5R(S/T) that falls within the catalytic domain of the enzyme (14). This PTP superfamily can further be divided into four categories on the basis of the amino sequence of the PTP catalytic domain, each with a range of substrate specificities PTPs (13).
Insulin Receptors in the Nucleus of the Solitary Tract and Related Neuronal Circuits
Published in I. Robin A. Barraco, Nucleus of the Solitary Tract, 2019
Unfortunately, the role of these molecules in insulin action is not clear and the fact that they have been implicated in the signal transduction pathways for other tyrosine kinase receptors further complicates the interpretation of the findings.25 This raises the point that there may be other neuron-specific processes by which the brain insulin receptor acts. It is clear that the amount of phosphotyrosine-containing proteins in neurons that contain insulin receptors is unusually high. Thus, protein substrates for the kinase activity of the insulin receptor other than IRS-1 may be relatively abundant, especially in receptor-rich areas like the NTS. Studies of such brain regions may help uncover the functions of insulin in the central nervous system and explain how insulin action is mediated in neurons.
Drug Targeting to the Lung: Chemical and Biochemical Considerations
Published in Anthony J. Hickey, Sandro R.P. da Rocha, Pharmaceutical Inhalation Aerosol Technology, 2019
Peter A. Crooks, Narsimha R. Penthala, Abeer M. Al-Ghananeem
In a structure-activity correlation study, a number of N-substituted derivatives of rolipram (52) were prepared and evaluated (Tanaka et al. 1995). A carbamate ester of rolipram was found to be approximately 10-fold more potent than rolipram itself at inhibiting human PDE IV. A methyl ketone derivative of rolipram showed more potent inhibition of PDE IV compared to rolipram or its carbamate ester. Based on proton NMR spectroscopy and computer modeling studies, a pharmacophore model of the methyl ketone derivative was proposed (Stafford et al. 1995). This model showed that the ketone carbonyl oxygen atom is involved in an important interaction within the PDE IV active site. Sodium orthovanadate, a phosphotyrosine phosphate inhibitor, exhibits dose- and time-dependent suppression of Lewis lung carcinoma A11 cell spreading. Protein tyrosine phosphorylation levels in A11 cells were elevated after treatment with ortho vanadate; this increase was partially diminished by the tyrosine kinase inhibitor ST 638, concomitantly with restoration of the suppressed cell spreading, as well as invasive and metastatic ability (Takenaga 1996). These results suggest tyrosine phosphorylation influences adhesion of cancer cells to lung surface endothelia, and that a valid approach in treating cancer is inhibition of phosphotyrosine phosphatase.
17β-Estradiol nongenomically induces vasodilation is enhanced by promoting phosphorylation of endophilin A2
Published in Gynecological Endocrinology, 2022
Xiao-Yun Liu, Ping Li, Xiao-Sa Li, Tommaso Simoncini, Yang Cheng
In order to investigate whether E2 could phosphorylation the tyrosine of Endo II, HUVECs were treated with E2 or its agonist and antagonist, then immunoprecipitation the cell lysates with anti-Endo II antibody. Finally, the immunoprecipitates were analyzed by western blotting with anti-Phosphotyrosine antibody. As shown in Figure 2A, when the cells were treated with E2 in different concentrations for 15 min, E2 induced tyrosine phosphorylation of Endo II at 1 nM–1μM. Also, E2 increased tyrosine phosphorylation of Endo II for 5 min–15min when the cells were treated with E2 at 10 nM and it declined at 30 min (Figure 2B). Therefore, E2 triggered tyrosine phosphorylation of Endo II in a concentration-dependent manner and a time-course effect. Furthermore, treatment of HUVECs with the ERα agonist PPT, but not the ERβ agonist DPN increased tyrosine phosphorylation of Endo II when compared to the cells treated with the DMSO control. Moreover, the effect elicited by E2 or PPT was abolished by ER antagonist ICI 182780 (Figure 2C). Together, these results suggested that the rapidly increased tyrosine phosphorylation of Endo II was involved in non-genomic pathways and ERβ is not implicated in the activation of Endo II.
Phosphoproteomics: a valuable tool for uncovering molecular signaling in cancer cells
Published in Expert Review of Proteomics, 2021
Jacqueline S. Gerritsen, Forest M. White
MS-based phosphoproteomics has the potential to uncover activated signaling networks and novel targets in cancer cells, yet there are some inherent challenges. For instance, phosphorylation is a reversible modification that can be highly dynamic on the seconds-to-minutes time scale [15]. Additionally, the phosphoproteome comprises approximately 0.1% of the proteome, and low-level phosphorylation events such as phosphotyrosine comprise only 0.1–1% of the phosphoproteome [15]; in many cases these ultra-low-abundance phosphorylation events are critical to decipher cellular signaling networks mediating oncogenic initiation and progression. Thus, MS-based phosphoproteomics must be able to identify and quantify ultra-low level, dynamic phosphorylation events. At the same time, some highly abundant proteins are phosphorylated at high stoichiometry, thus MS-based phosphoproteomics must also be able to handle a large dynamic range of phosphorylation.
Preclinical evaluation of AFM24, a novel CD16A-specific innate immune cell engager targeting EGFR-positive tumors
Published in mAbs, 2021
Susanne Wingert, Uwe Reusch, Stefan Knackmuss, Michael Kluge, Michael Damrat, Jens Pahl, Ute Schniegler-Mattox, Thomas Mueller, Ivica Fucek, Kristina Ellwanger, Michael Tesar, Torsten Haneke, Joachim Koch, Martin Treder, Wolfgang Fischer, Erich Rajkovic
The epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein belonging to the erbB family of tyrosine kinase receptors.1 Binding of EGFR to its ligands leads to activation of signal transduction pathways that are involved in regulating cellular proliferation, differentiation, and survival.1 Although also expressed by normal cells, EGFR is overexpressed in many solid tumors, including colorectal cancer (CRC), head and neck squamous cell carcinoma (HNSCC), and non–small cell lung cancer (NSCLC), and has been associated with poor prognosis and decreased survival.1 Multiple ligands bind to and activate EGFR, including amphiregulin, epiregulin, epidermal growth factor (EGF), and transforming growth factor-α.1,2 Ligand binding results in an extended conformation of the extracellular domain (ECD), which then promotes EGFR homo- or heterodimerization and a conformational change of the receptor resulting in the autophosphorylation of the intracellular tyrosine kinase domains. Phosphotyrosine residues then activate, either directly or through adaptor proteins, downstream components of signaling pathways including Ras/MAPK, PLCγ1/PKC, PI3 kinase/Akt, and STAT pathways.1,3,4