Lnk controls mouse hematopoietic stem cell self-renewal and quiescence through direct interactions with JAK2

J Clin Invest. 2008 Aug;118(8):2832-44. doi: 10.1172/JCI35808.


In addition to its role in megakaryocyte production, signaling initiated by thrombopoietin (TPO) activation of its receptor, myeloproliferative leukemia virus protooncogene (c-Mpl, or Mpl), controls HSC homeostasis and self-renewal. Under steady-state conditions, mice lacking the inhibitory adaptor protein Lnk harbor an expanded HSC pool with enhanced self-renewal. We found that HSCs from Lnk-/- mice have an increased quiescent fraction, decelerated cell cycle kinetics, and enhanced resistance to repeat treatments with cytoablative 5-fluorouracil in vivo compared with WT HSCs. We further provide genetic evidence demonstrating that Lnk controls HSC quiescence and self-renewal, predominantly through Mpl. Consistent with this observation, Lnk-/- HSCs displayed potentiated activation of JAK2 specifically in response to TPO. Biochemical experiments revealed that Lnk directly binds to phosphorylated tyrosine residues in JAK2 following TPO stimulation. Of note, the JAK2 V617F mutant, found at high frequencies in myeloproliferative diseases, retains the ability to bind Lnk. Therefore, we identified Lnk as a physiological negative regulator of JAK2 in stem cells and TPO/Mpl/JAK2/Lnk as a major regulatory pathway in controlling stem cell self-renewal and quiescence.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Cell Cycle / genetics
  • Enzyme Activation / drug effects
  • Fluorouracil / pharmacology
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / physiology*
  • Homeostasis
  • Homozygote
  • Intracellular Signaling Peptides and Proteins
  • Janus Kinase 2 / chemistry
  • Janus Kinase 2 / genetics
  • Janus Kinase 2 / metabolism*
  • Kinetics
  • Megakaryocytes / metabolism
  • Membrane Proteins
  • Mice
  • Mice, Knockout
  • Mutation
  • Phosphorylation
  • Proteins / genetics
  • Proteins / metabolism
  • Proteins / physiology*
  • Receptors, Thrombopoietin / physiology
  • Thrombopoietin / metabolism
  • Thrombopoietin / pharmacology
  • Tyrosine / metabolism


  • Adaptor Proteins, Signal Transducing
  • Intracellular Signaling Peptides and Proteins
  • Lnk protein, mouse
  • Membrane Proteins
  • Mpl protein, mouse
  • Proteins
  • Receptors, Thrombopoietin
  • Tyrosine
  • Thrombopoietin
  • Janus Kinase 2
  • Fluorouracil