A Src family kinase-Shp2 axis controls RUNX1 activity in megakaryocyte and T-lymphocyte differentiation

Genes Dev. 2012 Jul 15;26(14):1587-601. doi: 10.1101/gad.192054.112. Epub 2012 Jul 3.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / metabolism*
  • Cell Differentiation / physiology*
  • Cell Line
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism
  • Core Binding Factor Alpha 2 Subunit / genetics
  • Core Binding Factor Alpha 2 Subunit / metabolism*
  • GATA1 Transcription Factor / genetics
  • GATA1 Transcription Factor / metabolism
  • Hematopoiesis / physiology
  • Humans
  • Megakaryocytes / cytology
  • Megakaryocytes / metabolism*
  • Mice
  • Mice, Transgenic
  • Phosphorylation / physiology
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism*
  • Signal Transduction / physiology*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • src-Family Kinases / genetics
  • src-Family Kinases / metabolism*


  • Chromosomal Proteins, Non-Histone
  • Core Binding Factor Alpha 2 Subunit
  • GATA1 Transcription Factor
  • Gata1 protein, mouse
  • Runx1 protein, mouse
  • SWI-SNF-B chromatin-remodeling complex
  • Transcription Factors
  • src-Family Kinases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Ptpn11 protein, mouse