A novel DYRK1B inhibitor AZ191 demonstrates that DYRK1B acts independently of GSK3β to phosphorylate cyclin D1 at Thr286, not Thr288

2013 ◽  
Vol 457 (1) ◽  
pp. 43-56 ◽  
Author(s):  
Anne L. Ashford ◽  
David Oxley ◽  
Jason Kettle ◽  
Kevin Hudson ◽  
Sylvie Guichard ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cyclin D1 ◽  
Selective Inhibitor ◽  
First Time

We use AZ191, a novel selective inhibitor of the DYRK1B protein kinase to show for the first time that DYRK1B acts independently of GSK3β to phosphorylate CCND1 (cyclin D1) at Thr286 (not Thr288 as previously suggested), thereby promoting CCND1 turnover.

scholarly journals Characterization of VPS34-IN1, a selective inhibitor of Vps34, reveals that the phosphatidylinositol 3-phosphate-binding SGK3 protein kinase is a downstream target of class III phosphoinositide 3-kinase

2014 ◽  
Vol 463 (3) ◽  
pp. 413-427 ◽  
Author(s):  
Ruzica Bago ◽  
Nazma Malik ◽  
Michael J. Munson ◽  
Alan R. Prescott ◽  
Paul Davies ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Selective Inhibitor ◽  
Class Iii ◽  
Phosphate Binding ◽  
Downstream Target ◽  
Phosphoinositide 3 Kinase ◽  
Phosphatidylinositol 3

We characterize VPS34-IN, a potent and selective inhibitor of class III Vps34 PI3K. Using VPS34-IN1, we demonstrate that PtdIns(3)P, produced by Vps34 controls phosphorylation and activity of the SGK3 protein kinase.

scholarly journals Validation of the protein kinase PfCLK3 as a multistage cross-species malarial drug target

Science ◽  
2019 ◽  
Vol 365 (6456) ◽  
pp. eaau1682 ◽  
Author(s):  
Mahmood M. Alam ◽  
Ana Sanchez-Azqueta ◽  
Omar Janha ◽  
Erika L. Flannery ◽  
Amit Mahindra ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Protein Kinase ◽  
Rna Splicing ◽  
Drug Target ◽  
Selective Inhibitor ◽  
Molecular Pathways ◽  
Life Stages ◽  
Next Generation ◽  
Down Regulation ◽  
Transmission Blocking

The requirement for next-generation antimalarials to be both curative and transmission-blocking necessitates the identification of previously undiscovered druggable molecular pathways. We identified a selective inhibitor of the Plasmodium falciparum protein kinase PfCLK3, which we used in combination with chemogenetics to validate PfCLK3 as a drug target acting at multiple parasite life stages. Consistent with a role for PfCLK3 in RNA splicing, inhibition resulted in the down-regulation of more than 400 essential parasite genes. Inhibition of PfCLK3 mediated rapid killing of asexual liver- and blood-stage P. falciparum and blockade of gametocyte development, thereby preventing transmission, and also showed parasiticidal activity against P. berghei and P. knowlesi. Hence, our data establish PfCLK3 as a target for drugs, with the potential to offer a cure—to be prophylactic and transmission blocking in malaria.

Distinct PKC isoforms mediate cell survival and DNA synthesis in thrombin-induced myofibroblasts

2005 ◽  
Vol 288 (1) ◽  
pp. L190-L201 ◽  
Author(s):  
Galina S. Bogatkevich ◽  
Estella Gustilo ◽  
Jim C. Oates ◽  
Carol Feghali-Bostwick ◽  
Russell A. Harley ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Dna Synthesis ◽  
Cyclin D1 ◽  
Fas Ligand ◽  
De Novo ◽  
Regulatory Protein ◽  
Mitogen Activated Protein Kinase ◽  
Lung Fibroblasts ◽  
Normal Lung ◽  
Pkc Isoforms

Thrombin activates protease-activated receptor (PAR)-1 and induces a myofibroblast phenotype in normal lung fibroblasts that resembles the phenotype of scleroderma lung fibroblasts. We now demonstrate that PAR-1 expression is dramatically increased in lung tissue from scleroderma patients, where it is associated with inflammatory and fibroproliferative foci. We also observe that thrombin induces resistance to apoptosis in normal lung fibroblasts, and this process is regulated by protein kinase C (PKC)-ε but not by PKC-α. Overexpression of a constitutively active (c-a) form of PAR-1 or PKC-ε significantly inhibits Fas ligand-induced apoptosis in lung fibroblasts, whereas scleroderma lung fibroblasts are resistant to apoptosis de novo. Thrombin translocates p21Cip1/WAF1, a signaling molecule downstream of PKC, from the nucleus to cytoplasm in normal lung fibroblasts mimicking the localization of p21Cip1/WAF1 in scleroderma lung fibroblasts. Overexpression of c-a PKC-α or PKC-ε results in accumulation of p21Cip1/WAF1 in the cytoplasm. Depletion of PKC-α or inhibition of mitogen-activated protein kinase (MAPK) blocks thrombin-induced DNA synthesis in lung fibroblasts. Inhibition of PKC by calphostin or PKC-α, but not PKC-ε, by antisense oligonucleotides prevents thrombin-induced MAPK phosphorylation and accumulation of G1 phase regulatory protein cyclin D1, suggesting that PKC-α, MAPK, and cyclin D1 mediate lung fibroblast proliferation. These data demonstrate that two distinct PKC isoforms mediate thrombin-induced resistance to apoptosis and proliferation and suggest that p21Cip1/WAF1 promotes both phenomena.

scholarly journals Regulation of cyclin D1 expression and cell cycle progression by mitogen-activated protein kinase cascade

1999 ◽  
Vol 56 (4) ◽  
pp. 1258-1261 ◽  
Author(s):  
Yoshio Terada ◽  
Seiji Inoshita ◽  
Osamu Nakashima ◽  
Michio Kuwahara ◽  
Sei Sasaki ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Protein Kinase ◽  
Cyclin D1 ◽  
Cell Cycle Progression ◽  
Mitogen Activated Protein Kinase ◽  
Cycle Progression ◽  
Mitogen Activated Protein ◽  
Kinase Cascade ◽  
Protein Kinase Cascade

scholarly journals Cell Cycle Arrest and Reversion of Ras-Induced Transformation by a Conditionally Activated Form of Mitogen-Activated Protein Kinase Kinase Kinase 3

1999 ◽  
Vol 19 (5) ◽  
pp. 3857-3868 ◽  
Author(s):  
Heidrun Ellinger-Ziegelbauer ◽  
Kathleen Kelly ◽  
Ulrich Siebenlist
Keyword(s):  
Cell Cycle ◽  
Protein Kinase ◽  
Cyclin D1 ◽  
Stress Responses ◽  
Cell Cycle Progression ◽  
Cellular Transformation ◽  
Mitogen Activated Protein Kinase ◽  
Cycle Progression ◽  
Mapk Kinase ◽  
Mitogen Activated Protein

ABSTRACT Signal-induced proliferation, differentiation, or stress responses of cells depend on mitogen-activated protein kinase (MAPK) cascades, the core modules of which consist of members of three successively acting kinase families (MAPK kinase kinase [MAP3K], MAPK kinase, and MAPK). It is demonstrated here that the MEKK3 kinase inhibits cell proliferation, a biologic response not commonly associated with members of the MAP3K family of kinases. A conditionally activated form of MEKK3 stably expressed in fibroblasts arrests these cells in early G1. MEKK3 critically blocks mitogen-driven expression of cyclin D1, a cyclin which is essential for progression of fibroblasts through G1. The MEKK3-induced block of cyclin D1 expression and of cell cycle progression may be mediated via p38 MAPK, a downstream effector of MEKK3. The MEKK3-mediated block of proliferation also reverses Ras-induced cellular transformation, suggesting possible tumor-suppressing functions for this kinase. Together, these results suggest an involvement of the MEKK3 kinase in negative regulation of cell cycle progression, and they provide the first insights into biologic activities of this kinase.

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