Experimental Analysis of Receptor Kinase Phosphorylation

2011 ◽  
pp. 1-15 ◽  
Author(s):  
Srijeet K. Mitra ◽  
Michael B. Goshe ◽  
Steven D. Clouse
Keyword(s):  
Experimental Analysis ◽  
Receptor Kinase ◽  
Kinase Phosphorylation

scholarly journals Grb2 controls phosphorylation of FGFR2 by inhibiting receptor kinase and Shp2 phosphatase activity

2013 ◽  
Vol 200 (4) ◽  
pp. 493-504 ◽  
Author(s):  
Zamal Ahmed ◽  
Chi-Chuan Lin ◽  
Kin M. Suen ◽  
Fernando A. Melo ◽  
James A Levitt ◽  
...  
Keyword(s):  
Growth Factor ◽  
Phosphatase Activity ◽  
Tyrosine Phosphatase ◽  
Growth Factor Receptor ◽  
Adaptor Protein ◽  
Sh2 Domain ◽  
Receptor Kinase ◽  
Downstream Signaling ◽  
State Growth ◽  
Kinase Phosphorylation

Constitutive receptor tyrosine kinase phosphorylation requires regulation of kinase and phosphatase activity to prevent aberrant signal transduction. A dynamic mechanism is described here in which the adaptor protein, growth factor receptor–bound protein 2 (Grb2), controls fibroblast growth factor receptor 2 (FGFR2) signaling by regulating receptor kinase and SH2 domain–containing protein tyrosine phosphatase 2 (Shp2) phosphatase activity in the absence of extracellular stimulation. FGFR2 cycles between its kinase-active, partially phosphorylated, nonsignaling state and its Shp2-dephosphorylated state. Concurrently, Shp2 cycles between its FGFR2-phosphorylated and dephosphorylated forms. Both reciprocal activities of FGFR2 and Shp2 were inhibited by binding of Grb2 to the receptor. Phosphorylation of Grb2 by FGFR2 abrogated its binding to the receptor, resulting in up-regulation of both FGFR2’s kinase and Shp2’s phosphatase activity. Dephosphorylation of Grb2 by Shp2 rescued the FGFR2–Grb2 complex. This cycling of enzymatic activity results in a homeostatic, signaling-incompetent state. Growth factor binding perturbs this background cycling, promoting increased FGFR2 phosphorylation and kinase activity, Grb2 dissociation, and downstream signaling. Grb2 therefore exerts constitutive control over the mutually dependent activities of FGFR2 and Shp2.

scholarly journals Desensitization of β2-Adrenergic Receptors with Mutations of the Proposed G Protein-coupled Receptor Kinase Phosphorylation Sites

1998 ◽  
Vol 273 (13) ◽  
pp. 7637-7642 ◽  
Author(s):  
Antia Seibold ◽  
Bridgette G. January ◽  
Jacqueline Friedman ◽  
R. William Hipkin ◽  
Richard B. Clark
Keyword(s):  
G Protein ◽  
Adrenergic Receptors ◽  
Phosphorylation Sites ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
Kinase Phosphorylation ◽  
G Protein Coupled

scholarly journals Synthesis and Evaluation of 3-Substituted-4-(quinoxalin-6-yl) Pyrazoles as TGF-β Type I Receptor Kinase Inhibitors

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3369 ◽  
Author(s):  
Li-Min Zhao ◽  
Zhen Guo ◽  
Yi-Jie Xue ◽  
Jun Min ◽  
Wen-Jing Zhu ◽  
...  
Keyword(s):  
Map Kinase ◽  
Kinase Inhibitors ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Docking Study ◽  
Type I ◽  
Receptor Kinase ◽  
Molecular Docking Study ◽  
Mitogen Activated Protein ◽  
Kinase Phosphorylation

The transforming growth factor-β (TGF-β), in which overexpression has been associated with various diseases, has become an attractive molecular target for the treatment of cancers. Thirty-two quinoxaline-derivatives of 3-substituted-4-(quinoxalin-6-yl) pyrazoles 14a–d, 15a–d, 16a–d, 17a–d, 18a–d, 19a–d, 25a, 25b, 25d, 26a, 26b, 26d, 27b, and 27d were synthesized and evaluated for their activin TGF-β type I receptor kinase and p38α mitogen activated protein (MAP) kinase inhibitory activity in enzymatic assays. Among these compounds, the most active compound 19b inhibited TGF-β type I receptor kinase phosphorylation with an IC50 value of 0.28 µM, with 98% inhibition at 10 µM. Compound 19b also had good selectivity index of >35 against p38α MAP kinase, with 9.0-fold more selective than clinical candidate, compound 3 (LY-2157299). A molecular docking study was performed to identify the mechanism of action of the synthesized compounds and their good binding interactions were observed. ADMET prediction of good active compounds showed that these ones possess good pharmacokinetics and drug-likeness behavior.

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