mDYRK3 kinase is expressed selectively in late erythroid progenitor cells and attenuates colony-forming unit-erythroid development.
DYRKs are a new subfamily of dual-specificity kinases that was originally discovered on the basis of homology to Yak1, an inhibitor of cell cycle progression in yeast. At present, mDYRK-3 and mDYRK-2 have been cloned, and mDYRK-3 has been characterized with respect to kinase activity, expression among tissues and hematopoietic cells, and possible function during erythropoiesis. In sequence, mDYRK-3 diverges markedly in noncatalytic domains from mDYRK-2 and mDYRK-1a, but is 91.3% identical overall to hDYRK-3. Catalytically, mDYRK-3 readily phosphorylated myelin basic protein (but not histone 2B) and also appeared to autophosphorylate in vitro. Expression of mDYRK-1a, mDYRK-2, and mDYRK-3 was high in testes, but unlike mDYRK1a and mDYRK 2, mDYRK-3 was not expressed at appreciable levels in other tissues examined. Among hematopoietic cells, however, mDYRK-3 expression was selectively elevated in erythroid cell lines and primary pro-erythroid cells. In developmentally synchronized erythroid progenitor cells, expression peaked sharply following exposure to erythropoietin plus stem cell factor (SCF) (but not SCF alone), and in situ hybridizations of sectioned embryos revealed selective expression of mDYRK-3 in fetal liver. Interestingly, antisense oligonucleotides to mDYRK-3 were shown to significantly and specifically enhance colony-forming unit-erythroid colony formation. Thus, it is proposed that mDYRK-3 kinase functions as a lineage-restricted, stage-specific suppressor of red cell development. (Blood. 2001;97:901-910)
Geiger
J N
JN
Department of Biochemistry & Molecular Biology and Veterinary Science, The Pennsylvania State University, University Park, PA, USA.
Knudsen
G T
GT
Panek
L
L
Pandit
A K
AK
Yoder
M D
MD
Lord
K A
KA
Creasy
C L
CL
Burns
B M
BM
Gaines
P
P
Dillon
S B
SB
Wojchowski
D M
DM
D016475:3T3 Cells / Q000201:enzymology; D000818:Animals; D019070:Cell Lineage; D003114:Colony-Forming Units Assay; D018076:DNA, Complementary / Q000235:genetics; D004357:Drug Synergism; D004790:Enzyme Induction; D015672:Erythroid Precursor Cells / Q000201:enzymology*; D004920:Erythropoiesis / Q000235:genetics*; D004921:Erythropoietin / Q000494:pharmacology; D005326:Fetal Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics; D004915:Leukemia, Erythroblastic, Acute / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics; D009928:Organ Specificity; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D019089:Stem Cell Factor / Q000494:pharmacology; D013379:Substrate Specificity; D014407:Tumor Cells, Cultured / Q000201:enzymology; D000097603:Dyrk Kinases
D018076:DNA, Complementary; D004921:Erythropoietin; D005326:Fetal Proteins; D007527:Isoenzymes; D009363:Neoplasm Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D019089:Stem Cell Factor; D000097603:Dyrk Kinases