Lnk controls mouse hematopoietic stem cell self-renewal and quiescence through direct interactions with JAK2.
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.
Bersenev
Alexey
A
Division of Hematology, Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-4318, USA.
Wu
Chao
C
Balcerek
Joanna
J
Tong
Wei
W
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D005472:Fluorouracil / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D006706:Homeostasis; D006720:Homozygote; D047908:Intracellular Signaling Peptides and Proteins; D053614:Janus Kinase 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007700:Kinetics; D008533:Megakaryocytes / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010766:Phosphorylation; D011506:Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D053628:Receptors, Thrombopoietin / Q000502:physiology; D013926:Thrombopoietin / Q000378:metabolism / Q000494:pharmacology; D014443:Tyrosine / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; C490777:Lnk protein, mouse; D008565:Membrane Proteins; C481270:Mpl protein, mouse; D011506:Proteins; D053628:Receptors, Thrombopoietin; D014443:Tyrosine; D013926:Thrombopoietin; D053614:Janus Kinase 2; D005472:Fluorouracil