Therapeutic challenges of kinase and phosphatase inhibition and use in anti-diabetic strategy

2005 ◽  
Vol 33 (2) ◽  
pp. 343-345 ◽  
Author(s):  
A.J. Bridges

The development of kinase and phosphatase inhibitors as novel therapeutic agents has been stimulated by the discovery that most biological processes are controlled by the reversible phosphorylation of proteins. Most of the early results in this area were generated in oncology, at the same time as the human genome, with its 500+ kinases and 100+ phosphatases was deciphered. Because of this, we know a great deal about which processes signalling inhibitors interfere with, but little about the overall consequences. In this study, kinases will be briefly reviewed, followed by some of the early problems in developing kinase inhibitors, as biochemical reagents, and clinically active pharmaceuticals in oncology. The discussion will then switch to the potential role of kinases and phosphatases in controlling the disease process in Type II diabetes. Phosphatase inhibitors should augment insulin receptor tyrosine kinase signalling. Glycogen synthesis and glycogenolysis are phosphorylation dependent, and amenable to kinase inhibition, as are some nuclear hormone receptors, and these will be briefly discussed.

2017 ◽  
Vol 15 (5) ◽  
pp. 421-423 ◽  
Author(s):  
Juan Ambrosioni ◽  
Mayte Coiras ◽  
José Alcamí ◽  
José M. Miró

2020 ◽  
Vol 83 (1) ◽  
pp. e65 ◽  
Author(s):  
Maddalena Napolitano ◽  
Gabriella Fabbrocini ◽  
Cataldo Patruno

2016 ◽  
Vol 230 (1) ◽  
pp. R1-R11 ◽  
Author(s):  
Anthony H Tsang ◽  
Mariana Astiz ◽  
Maureen Friedrichs ◽  
Henrik Oster

Endogenous circadian clocks regulate 24-h rhythms of behavior and physiology to align with external time. The endocrine system serves as a major clock output to regulate various biological processes. Recent findings suggest that some of the rhythmic hormones can also provide feedback to the circadian system at various levels, thus contributing to maintaining the robustness of endogenous rhythmicity. This delicate balance of clock–hormone interaction is vulnerable to modern lifestyle factors such as shiftwork or high-calorie diets, altering physiological set points. In this review, we summarize the current knowledge on the communication between the circadian timing and endocrine systems, with a focus on adrenal glucocorticoids and metabolic peptide hormones. We explore the potential role of hormones as systemic feedback signals to adjust clock function and their relevance for the maintenance of physiological and metabolic circadian homeostasis.


1995 ◽  
Vol 6 (2) ◽  
pp. 119-131 ◽  
Author(s):  
K.R. Purushotham ◽  
M.G. Humphreys-Beher

Tyrosine phosphorylation and the intracellular signaling processes associated with it have been the focus of intense study due to its importance in the regulation of biological processes as diverse as cell proliferation and cell differentiation. While much of what we now understand has been derived from the study of cell lines and tumor cells, the salivary glands provide a model to examine the effects of tyrosine kinases and tyrosine phosphatases in a normal differentiated tissue. This review will focus, therefore, on the role tyrosine kinases and phosphatases play in inducing the transition from stasis to active proliferation and their potential role in mediating secretory function of the salivary glands.


2011 ◽  
Vol 286 (27) ◽  
pp. 24079-24088 ◽  
Author(s):  
Constanza Contreras-Jurado ◽  
Laura García-Serrano ◽  
Mariana Gómez-Ferrería ◽  
Clotilde Costa ◽  
Jesús M. Paramio ◽  
...  

We have analyzed the role of the thyroid hormone receptors (TRs) in epidermal homeostasis. Reduced keratinocyte proliferation is found in interfollicular epidermis of mice lacking the thyroid hormone binding isoforms TRα1 and TRβ (KO mice). Similar results were obtained in hypothyroid animals, showing the important role of the liganded TRs in epidermal proliferation. In addition, KO and hypothyroid animals display decreased hyperplasia in response to 12-O-tetradecanolyphorbol-13-acetate. Both receptor isoforms play overlapping functional roles in the skin because mice lacking individually TRα1 or TRβ also present a proliferative defect but not as marked as that found in double KO mice. Defective proliferation in KO mice is associated with reduction of cyclin D1 expression and up-regulation of the cyclin-dependent kinase inhibitors p19 and p27. Paradoxically, ERK and AKT activity and expression of downstream targets, such as AP-1 components, are increased in KO mice. Increased p65/NF-κB and STAT3 phosphorylation and, as a consequence, augmented expression of chemokines and proinflammatory cytokines is also found in these animals. These results show that thyroid hormones and their receptors are important mediators of skin proliferation and demonstrate that TRs act as endogenous inhibitors of skin inflammation, most likely due to interference with AP-1, NF-κB, and STAT3 activation.


2020 ◽  
Vol 5 (47) ◽  
pp. eabc5367 ◽  
Author(s):  
Francesca Romana Spinelli ◽  
Fabrizio Conti ◽  
Massimo Gadina

JAK kinase inhibitors are being investigated as a way of managing cytokine storm in severe COVID-19 patients.


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