造血干祖細胞(HSPC)的功能被復雜的信號網絡所控制,。研究發(fā)現(xiàn),，在造血作用期間，絡氨酸激酶JAK2在細胞因子信號網絡中起著非常重要的作用,。
銜接蛋白LNK是造血作用的一個決定性因素,，通過它與JAK2的抑制性相互作用，限制了HSPC的自我更新,。在老鼠模型,，LNK的缺陷促進了骨髓增生性腫瘤(MPN)的發(fā)展。而且,，在人類MPNs,，還發(fā)現(xiàn)了LNK的功能缺失突變。這些結果表明,，LNK在正常的及惡性的HSPCs中具有重要作用,。
這里，美國賓夕法尼亞大學佩雷爾曼醫(yī)學院的研究人員發(fā)現(xiàn),，14-3-3蛋白為LNK結合元件,，通過干涉LNK-JAK2的相互作用，能夠緩和LNK對JAK2信號及細胞增殖的抑制作用,。
研究發(fā)現(xiàn),，14-3-3的結合需要兩個位于LNK的絲氨酸磷酸化位點，而且它們的磷酸化是由糖原合酶激酶3及PKA激酶所介導,。
這些殘基的突變會終止LNK-JAK2的相互作用,，促進LNK的抑制作用。相反的,，強迫14-3-3與LCK的結合會限制LNK的功能,。
此外，與14-3-3的相互作用會使得在位于細胞質的LNK遠離細胞膜鄰近的JAK2,。重要的是,，骨髓移植研究表明，當LNK缺陷時,，14-3-3對HSPC的重構能夠部分緩和,。
總的來說，這項研究表明14-3-3蛋白通過影響LNK/JAK2通路,，成為了一個新的有效的HSPC調節(jié)因子,。相關論文發(fā)表在5月1日的The Journal of Clinical Investigation。（生物谷Deepblue編譯）
doi: 10.1172/JCI59719
PMC:
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.
