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 d iscovered on the basis of homology to Yak1, an inhibitor of cell cycle prog ression in yeast. At present, mDYRK-3 and mDYRK-2 have been cloned, and mDY RK-3 has been characterized with respect to kinase activity, expression amo ng tissues and hematopoietic cells, and possible function during erythropoi esis, In sequence, mDYRK-3 diverges markedly in noncatalytic domains from m DYRK-2 and mDYRK-1a, but is 91.3% identical overall to hDYRK-3. Catalytical ly, 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, mD YRK-3 was not expressed at appreciable levels in other tissues examined. Am ong hematopoietic cells, however, mDYRK-3 expression was selectively elevat ed in erythroid cell lines and primary pro-erythroid cells. In developmenta lly synchronized erythroid progenitor cells, expression peaked sharply foll owing exposure to erythropoietin plus stem cell factor (SCF) (but not SCF a lone), and in situ hybridizations of sectioned embryos revealed selective e xpression of mDYRK-3 in fetal liver. Interestingly, antisense oligonucleoti des 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. (C) 2001 by The American Society of Hematology.