A Src family kinase–Shp2 axis controls RUNX1 activity in megakaryocyte and T-lymphocyte differentiation
- Hui Huang1,
- Andrew J. Woo1,
- Zachary Waldon2,
- Yocheved Schindler1,
- Tyler B. Moran1,
- Helen H. Zhu3,
- Gen-Sheng Feng3,
- Hanno Steen2 and
- Alan B. Cantor1,4,5
- 1Department of Pediatric Hematology-Oncology, Children's Hospital Boston, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;
- 2Department of Pathology, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA;
- 3Department of Pathology, University of California at San Diego School of Medicine, La Jolla, California 92093, USA;
- 4Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA
Abstract
Hematopoietic development occurs in complex microenvironments and is influenced by key signaling events. Yet how these pathways communicate with master hematopoietic transcription factors to coordinate differentiation remains incompletely understood. The transcription factor RUNX1 plays essential roles in definitive hematopoietic stem cell (HSC) ontogeny, HSC maintenance, megakaryocyte (Mk) maturation, and lymphocyte differentiation. It is also the most frequent target of genetic alterations in human leukemia. Here, we report that RUNX1 is phosphorylated by Src family kinases (SFKs) and that this occurs on multiple tyrosine residues located within its negative regulatory DNA-binding and autoinhibitory domains. Retroviral transduction, chemical inhibitor, and genetic studies demonstrate a negative regulatory role of tyrosine phosphorylation on RUNX1 activity in Mk and CD8 T-cell differentiation. We also demonstrate that the nonreceptor tyrosine phosphatase Shp2 binds directly to RUNX1 and contributes to its dephosphorylation. Last, we show that RUNX1 tyrosine phosphorylation correlates with reduced GATA1 and enhanced SWI/SNF interactions. These findings link SFK and Shp2 signaling pathways to the regulation of RUNX1 activity in hematopoiesis via control of RUNX1 multiprotein complex assembly.
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Footnotes
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↵5 Corresponding author
E-mail alan.cantor{at}childrens.harvard.edu
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.192054.112.
- Received March 14, 2012.
- Accepted June 1, 2012.
- Copyright © 2012 by Cold Spring Harbor Laboratory Press