造血干祖细胞(HSPC)的功能被复杂的信号网络所控制。研究发现，在造血作用期间，络氨酸激酶JAK2在细胞因子信号网络中起着非常重要的作用。
衔接蛋白LNK是造血作用的一个决定性因素，通过它与JAK2的抑制性相互作用，限制了HSPC的自我更新。在老鼠模型，LNK的缺陷促进了骨髓增生性肿瘤(MPN)的发展。而且，在人类MPNs，还发现了LNK的功能缺失突变。这些结果表明，LNK在正常的及恶性的HSPCs中具有重要作用。
这里，美国宾夕法尼亚大学佩雷尔曼医学院的研究人员发现，14-3-3蛋白为LNK结合元件，通过干涉LNK-JAK2的相互作用，能够缓和LNK对JAK2信号及细胞增殖的抑制作用。
研究发现，14-3-3的结合需要两个位于LNK的丝氨酸磷酸化位点，而且它们的磷酸化是由糖原合酶激酶3及PKA激酶所介导。
这些残基的突变会终止LNK-JAK2的相互作用，促进LNK的抑制作用。相反的，强迫14-3-3与LCK的结合会限制LNK的功能。
此外，与14-3-3的相互作用会使得在位于细胞质的LNK远离细胞膜邻近的JAK2。重要的是，骨髓移植研究表明，当LNK缺陷时，14-3-3对HSPC的重构能够部分缓和。
总的来说，这项研究表明14-3-3蛋白通过影响LNK/JAK2通路，成为了一个新的有效的HSPC调节因子。相关论文发表在5月1日的The Journal of Clinical Investigation。（生物谷Deepblue编译）
doi: 10.1172/JCI59719
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PMID:
14-3-3 regulates the LNK/JAK2 pathway in mouse hematopoietic stem and progenitor cells
Jing Jiang, Joanna Balcerek, Krasimira Rozenova, Ying Cheng, Alexey Bersenev, Chao Wu, Yiwen Song and Wei Tong.
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.
