Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands.
J Proteome Res. 2011 Aug 5;10(8):3542-50. doi: 10.1021/pr2001594. Epub 2011 Jun 28.
The changes in signal transduction associated with the acquisition of specific cell fates remain poorly understood. We performed massive parallel assessment of kinase signatures of the radiations of the hematopoietic system, including long-term repopulating hematopoietic stem cells (LT-HSC), short-term repopulating HSC (ST-HSC), immature natural killer (iNK) cells, NK cells, B cells, T cells, and myeloid cells. The LT-HSC kinome is characterized by noncanonical Wnt, Ca(2+) and classical protein kinase C (PKC)-driven signaling, which is lost upon the transition to ST-HSC, whose kinome signature prominently features receptor tyrosine kinase (RTK) activation of the Ras/MAPK signaling cassette. Further differentiation to iNK maintains signaling through this cassette but simultaneously leads to activation of a PI3K/PKB/Rac signaling, which becomes the dominant trait in the kinase signature following full differentiation toward NK cells. Differentiation along the myeloid and B cell lineages is accompanied by hyperactivation of both the Ras/MAPK and PI3K/PKB/Rac signaling cassette. T cells, however, deactivate signaling and only display residual G protein-coupled pathways. Thus, differentiation along the hematopoietic lineage is associated with major remodelling of cellular kinase signature.
信号转导的变化与特定细胞命运的获得仍然知之甚少。我们对造血系统的辐射进行了大规模平行评估，包括长期重建成血细胞干细胞 (LT-HSC)、短期重建成血细胞干细胞 (ST-HSC)、未成熟自然杀伤 (iNK) 细胞、NK 细胞、B 细胞、T 细胞和髓样细胞。LT-HSC 的激酶组学的特征是非典型 Wnt、Ca(2+) 和经典蛋白激酶 C (PKC) 驱动的信号转导，而这种信号转导在向 ST-HSC 过渡时丢失，其激酶组学特征突出表现为受体酪氨酸激酶 (RTK) 激活 Ras/MAPK 信号盒。进一步向 iNK 分化维持通过该盒的信号传导，但同时导致 PI3K/PKB/Rac 信号传导的激活，在完全分化为 NK 细胞后，该信号传导成为激酶特征的主要特征。沿髓系和 B 细胞谱系的分化伴随着 Ras/MAPK 和 PI3K/PKB/Rac 信号盒的过度激活。然而，T 细胞失活信号传导，仅显示残留的 G 蛋白偶联途径。因此，造血谱系的分化与细胞激酶特征的重大重塑有关。
