PMID:18618018

Citation	Bersenev, A, Wu, C, Balcerek, J and Tong, W (2008) Lnk controls mouse hematopoietic stem cell self-renewal and quiescence through direct interactions with JAK2. J. Clin. Invest. 118:2832-44
Abstract	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.
Links	PubMed PMC2447929 Online version:10.1172/JCI35808
Keywords	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; Mice; Mice, Knockout; Mutation; Phosphorylation; Proteins/genetics; Proteins/metabolism; Proteins/physiology; Receptors, Thrombopoietin/physiology; Thrombopoietin/metabolism; Thrombopoietin/pharmacology; Tyrosine/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:HXK1	acts_upstream_of_or_within	GO:0061621: canonical glycolysis	ECO:0000305: curator inference used in manual assertion	GO:0004340	P	occurs_in:(CL:0000019)	Seeded From UniProt	complete

References

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