Binding of stromal derived factor-1alpha (SDF-1alpha) to CXCR4 chemokine receptor in normal human megakaryoblasts but not in platelets induces phosphorylation of mitogen-activated protein kinase p42/44 (MAPK), ELK-1 transcription factor and serine/threonine kinase AKT.
The aim of this study was to identify pathways which are involved in signal transduction from the CXCR4 receptor stimulated by stromal derived factor-1alpha (SDF-1alpha) in human malignant hematopoietic cells and normal megakaryoblasts. First, we found that activation of CXCR4 in human T cell lines (Jurkat and ATL-2) rapidly induced phosphorylation of mitogen-activated protein kinases (MAPK) (p44 ERK-1 and p42 ERK-2). Next, we became interested in CXCR4-mediated signaling in normal hematopoietic cells, and employed human megakaryoblasts, which highly express CXCR4 as a model. We found that stimulation of these cells with SDF-1alpha led to the phosphorylation of MAPK and serine/threonine kinase AKT as well. Activation of MAPK further led to the phosphorylation of the nuclear transcription factor ELK-1. Phosphorylation of ELK-1 in megakaryoblasts implies that phosphorylated MAPK translocate from cytoplasm into the nucleus where they may phosphorylate some nuclear proteins. Note that neither MAPK nor AKT was phosphorylated in normal human platelets after stimulation by SDF-1. We conclude that both MAPK and AKT are involved in signal transduction pathways from the CXCR4 receptor in malignant and normal human hematopoietic cells. The biological consequences of MAPK, ELK-1 and AKT phosphorylation in megakaryoblasts after stimulation with SDF-1alpha require further studies.
Majka
M
M
Department of Internal Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
Ratajczak
J
J
Kowalska
M A
MA
Ratajczak
M Z
MZ
D001792:Blood Platelets / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism* / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte; D004268:DNA-Binding Proteins; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D015459:Leukemia-Lymphoma, Adult T-Cell; D008533:Megakaryocytes / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured; D050807:ets-Domain Protein Elk-1
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D004268:DNA-Binding Proteins; C494112:ELK1 protein, human; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D019718:Receptors, CXCR4; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D002118:Calcium