title: 14-3-3 regulates the LNK/JAK2 pathway in mouse hematopoietic stem and             progenitor cells.
abstract: Hematopoietic stem and progenitor cell (HSPC) functions are governed by intricate             signaling networks. The tyrosine kinase JAK2 plays an essential role in cytokine             signaling during hematopoiesis. The adaptor protein LNK is a critical determinant of             this process through its inhibitory interaction with JAK2, thereby limiting HSPC             self-renewal. LNK deficiency promotes myeloproliferative neoplasm (MPN) development in             mice, and LNK loss-of-function mutations are found in human MPNs, emphasizing its             pivotal role in normal and malignant HSPCs. Here, we report the identification of 14-3-3             proteins as LNK binding partners. 14-3-3 interfered with the LNK-JAK2 interaction,             thereby alleviating LNK inhibition of JAK2 signaling and cell proliferation. Binding of             14-3-3 required 2 previously unappreciated serine phosphorylation sites in LNK, and we             found that their phosphorylation is mediated by glycogen synthase kinase 3 and PKA             kinases. Mutations of these residues abrogated the interaction and augmented the growth             inhibitory function of LNK. Conversely, forced 14-3-3 binding constrained LNK function.             Furthermore, interaction with 14-3-3 sequestered LNK in the cytoplasm away from the             plasma membrane-proximal JAK2. Importantly, bone marrow transplantation studies revealed             an essential role for 14-3-3 in HSPC reconstitution that can be partially mitigated by             LNK deficiency. We believe that, together, this work implicates 14-3-3 proteins as novel             and positive HSPC regulators by impinging on the LNK/JAK2 pathway.
authors.affiliation: Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104-4318, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Jiang
authors.forename: Joanna
authors.initials: J
authors.lastname: Balcerek
authors.forename: Krasimira
authors.initials: K
authors.lastname: Rozenova
authors.forename: Ying
authors.initials: Y
authors.lastname: Cheng
authors.forename: Alexey
authors.initials: A
authors.lastname: Bersenev
authors.forename: Chao
authors.initials: C
authors.lastname: Wu
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Song
authors.forename: Wei
authors.initials: W
authors.lastname: Tong
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D009196:Myeloproliferative Disorders / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D015398:Signal Transduction; D014184:Transplantation, Homologous
chemical_list: D048948:14-3-3 Proteins; D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; C490777:Lnk protein, mouse; D008565:Membrane Proteins; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D017868:Cyclic AMP-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3