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- Title
14-3-3 regulates the LNK/JAK2 pathway in mouse hematopoietic stem and progenitor cells.
- Authors
Jing Jiang; Balcerek, Joanna; Rozenova, Krasimira; Ying Cheng; Bersenev, Alexey; Chao Wu; Yiwen Song; Wei Tong
- 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.
- Subjects
HEMATOPOIETIC stem cells; PROGENITOR cells; CELLULAR signal transduction; PHOSPHORYLATION; MYELOPROLIFERATIVE neoplasms; HEMATOPOIESIS; GLYCOGEN synthase kinase-3
- Publication
Journal of Clinical Investigation, 2012, Vol 122, Issue 6, p2079
- ISSN
0021-9738
- Publication type
Article
- DOI
10.1172/JCI59719