Disabled-2 is transcriptionally regulated by ICSBP and augments macrophage spreading and adhesion.
Mice lacking transcription factor interferon consensus sequence binding protein (ICSBP) develop a syndrome similar to human chronic myeloid leukemia and are immunodeficient. In order to define the molecular mechanisms responsible for the cellular defects of ICSBP(-/-) mice, we used bone marrow-derived macrophages (BMM) to identify genes deregulated in the absence of ICSBP. Here, we report that disabled-2 (Dab2), a signal phosphoprotein, is transcriptionally up-regulated and accumulates in the cytoskeleton/membrane fraction of ICSBP(-/-) BMM. Moreover, our results revealed Dab2 as a novel IFN-gamma-response gene. Both ICSBP and the Ets-transcription factor PU.1 bind to the Dab2 promoter, whereby ICSBP represses PU.1-induced Dab2 promoter transactivation in vitro. Notably, repression of Dab2 expression by ICSBP is also found in myeloid progenitors. Overexpression of Dab2 leads to accelerated cell adhesion and spreading, accompanied by enhanced actin fiber formation. Furthermore, cell adhesion induces transient Dab2 phosphorylation and its translocation to the cytoskeletal/membrane fraction. Our results identify a novel role of Dab2 as an inducer of cell adhesion and spreading, and strongly suggest that the up-regulation of Dab2 contributes to the hematopoietic defect seen in ICSBP(-/-) mice.
Rosenbauer
Frank
F
Department of Molecular Genetics, Institute of Molecular Pharmacology, and Benjamin Franklin Medical Center, Free University of Berlin, Krahmerstrasse 6, D-12207 Berlin, Germany.
Kallies
Axel
A
Scheller
Marina
M
Knobeloch
Klaus-Peter
KP
Rock
Charles O
CO
Schwieger
Maike
M
Stocking
Carol
C
Horak
Ivan
I
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002448:Cell Adhesion / Q000235:genetics; D016147:Genes, Tumor Suppressor; D006410:Hematopoiesis / Q000235:genetics; D006801:Humans; D050835:Interferon Regulatory Factors; D020014:K562 Cells; D008264:Macrophages / Q000166:cytology / Q000502:physiology*; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics; D011506:Proteins / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins; D015854:Up-Regulation; D000099185:Interferon Regulatory Factor-8; D000099232:Proto-Oncogene Protein Spi-1
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D051017:Apoptosis Regulatory Proteins; D050835:Interferon Regulatory Factors; D011506:Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D000099185:Interferon Regulatory Factor-8; D000099232:Proto-Oncogene Protein Spi-1; C102885:DAB2 protein, human