DYRK3 Activation, Engagement of Protein Kinase A/cAMP Response Element-binding Protein, and Modulation of Progenitor Cell Survival

DYRKs are a new family ofdual-specificity tyrosine-regulatedkinases with emerging roles in cell growth and development. Recently, we discovered that DYRK3 is expressed primarily in erythroid progenitor cells and modulates late erythropoiesis. We now describe 1) roles for the DYRK3 YTY signature moti...

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Veröffentlicht in:The Journal of biological chemistry 2002-12, Vol.277 (49), p.47052-47060
Hauptverfasser: Li, Ke, Zhao, Shuqing, Karur, Vinit, Wojchowski, Don M.
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container_end_page 47060
container_issue 49
container_start_page 47052
container_title The Journal of biological chemistry
container_volume 277
creator Li, Ke
Zhao, Shuqing
Karur, Vinit
Wojchowski, Don M.
description DYRKs are a new family ofdual-specificity tyrosine-regulatedkinases with emerging roles in cell growth and development. Recently, we discovered that DYRK3 is expressed primarily in erythroid progenitor cells and modulates late erythropoiesis. We now describe 1) roles for the DYRK3 YTY signature motif in kinase activation, 2) the coupling of DYRK3 to cAMP response element (CRE)-binding protein (CREB), and 3) effects of DYRK3 on hematopoietic progenitor cell survival. Regarding the DYRK3 kinase domain, intactness of Tyr333 (but not Tyr331) within subdomain loop VII–VIII was critical for activation. Tyr331 plus Tyr333 acidification (Tyr mutated to Glu) was constitutively activating, but kinase activity was not affected substantially by unique N- or C-terminal domains. In transfected 293 and HeLa cells, DYRK3 was discovered to efficiently stimulate CRE-luciferase expression, to activate a CREB-Gal4 fusion protein, and to promote CREB phosphorylation at Ser133. Interestingly, this CREB/CRE response was also supported (50% of wild-type activity) by a kinase-inactive DYRK3 mutant as well as a DYRK3 C-terminal region and was blocked by protein kinase A inhibitors, suggesting functional interactions between protein kinase A and DYRK3. Finally, DYRK3 expression in cytokine-dependent hematopoietic FDCW2 cells was observed to inhibit programmed cell death. Thus, primary new insight into DYRK3 kinase signaling routes, subdomain activities, and possible biofunctions is provided.
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subjects Amino Acid Motifs
Amino Acid Sequence
Animals
Apoptosis
Blotting, Western
Cell Death
Cell Line
Cell Survival
COS Cells
Cyclic AMP Response Element-Binding Protein - metabolism
Cyclic AMP-Dependent Protein Kinases - metabolism
Cytokines - metabolism
DNA, Complementary - metabolism
Dyrk Kinases
Flow Cytometry
Genes, Reporter
HeLa Cells
Hematopoietic Stem Cells - metabolism
Humans
Mice
Models, Biological
Molecular Sequence Data
Phosphorylation
Precipitin Tests
Protein Binding
Protein Serine-Threonine Kinases - metabolism
Protein Structure, Tertiary
Protein-Tyrosine Kinases - metabolism
Sequence Homology, Amino Acid
Serine - metabolism
Signal Transduction
Time Factors
Transfection
Tyrosine - chemistry
title DYRK3 Activation, Engagement of Protein Kinase A/cAMP Response Element-binding Protein, and Modulation of Progenitor Cell Survival
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