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Hematopoietic stem and progenitor cell (HSPC) functions are governed by intricatesignaling networks. The tyrosine kinase JAK2 plays an essential role in cytokinesignaling during hematopoiesis. The adaptor protein LNK is a critical determinant ofthis process through its inhibitory interaction with JAK2, thereby limiting HSPCself-renewal. LNK deficiency promotes myeloproliferative neoplasm (MPN) development inmice, and LNK loss-of-function mutations are found in human MPNs, emphasizing itspivotal role in normal and malignant HSPCs. Here, we report the identification of 14-3-3proteins as LNK binding partners. 14-3-3 interfered with the LNK-JAK2 interaction,thereby alleviating LNK inhibition of JAK2 signaling and cell proliferation. Binding of14-3-3 required 2 previously unappreciated serine phosphorylation sites in LNK, and wefound that their phosphorylation is mediated by glycogen synthase kinase 3 and PKAkinases. Mutations of these residues abrogated the interaction and augmented the growthinhibitory 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 theplasma membrane-proximal JAK2. Importantly, bone marrow transplantation studies revealedan essential role for 14-3-3 in HSPC reconstitution that can be partially mitigated byLNK deficiency. We believe that, together, this work implicates 14-3-3 proteins as noveland positive HSPC regulators by impinging on the LNK/JAK2 pathway.

14-3-3 regulates the LNK/JAK2 pathway in mouse hematopoietic stem and progenitor cells