Mitogen-activated protein kinase mediates erythropoietin-induced phosphorylation of the TAL1/SCL transcription factor in murine proerythroblasts.

Tang T, Prasad KS, Koury MJ, Brandt SJ
Biochem J. 1999 343 Pt 3: 615-20

PMID: 10527940 · PMCID: PMC1220593

Ectopic expression of the basic helix-loop-helix transcription factor TAL1 (or SCL) is the most frequent gain-of-function mutation in T-cell acute lymphoblastic leukaemia. Gene-knockout studies in mice have demonstrated that TAL1 is required for embryonic and adult haematopoiesis, and considerable evidence suggests it also has important functions in terminal erythroid differentiation. We reported previously that TAL1 phosphorylation is stimulated by erythropoietin in splenic proerythroblasts isolated from mice infected with the anaemia-inducing strain of Friend virus and show here the signalling pathway responsible. Erythropoietin was found to stimulate nuclear mitogen-activated protein kinase activity in addition to TAL1 protein phosphorylation, both of which were quantitatively inhibited by the mitogen-activated protein kinase kinase inhibitor PD 098059 and the phosphatidylinositol 3-kinase inhibitor wortmannin. Tryptic phosphopeptide analysis of radiolabelled TAL1 immunoprecipitated from nuclear extracts of Friend virus-induced proerythroblasts revealed that phosphorylation of Ser(122), shown previously to be a substrate for the mitogen-activated protein kinase ERK1 (extracellular signal-regulated protein kinase) in vitro, was specifically, although not exclusively, increased by erythropoietin and inhibited by wortmannin and PD 098059. These results are consistent with an erythropoietin-stimulated signalling pathway in which there is direct activation of a mitogen-activated protein kinase kinase by phosphatidylinositol 3-kinase and identify TAL1 as one of its nuclear targets. These data suggest, in addition, a specific mechanism by which the principal regulator of erythroid differentiation could enhance TAL1 function, in addition to increasing its expression.

MeSH Terms (23)

Androstadienes Anemia Animals Basic Helix-Loop-Helix Transcription Factors DNA-Binding Proteins Enzyme Inhibitors Erythroblasts Flavonoids Friend murine leukemia virus Hematopoietic Stem Cells Mice Mice, Inbred Strains Mitogen-Activated Protein Kinases Mutagenesis, Site-Directed Phosphopeptides Phosphorylation Phosphoserine Proto-Oncogene Proteins Recombinant Proteins Spleen T-Cell Acute Lymphocytic Leukemia Protein 1 Transcription Factors Wortmannin

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