Li Jing, Zhang Jun, Tang Minghui, Xin Junping, Xu Yan, Volk Andrew, Hao Caiqin, Hu Chenglong, Sun Jiewen, Wei Wei, Cao Quichan, Breslin Peter, Zhang Jiwang
Department of Biology, College of Life and Environment Science, Shanghai Normal University, Shanghai, People's Republic of China.
Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Chicago, Illinois, USA.
Stem Cells. 2016 Aug;34(8):2130-44. doi: 10.1002/stem.2382. Epub 2016 May 19.
The phosphorylated form of Pten (p-Pten) is highly expressed in >70% of acute myeloid leukemia samples. However, the role of p-Pten in normal and abnormal hematopoiesis has not been studied. We found that Pten protein levels are comparable among long-term (LT) hematopoietic stem cells (HSCs), short-term (ST) HSCs, and multipotent progenitors (MPPs); however, the levels of p-Pten are elevated during the HSC-to-MPP transition. To study whether p-Pten is involved in regulating self-renewal and differentiation in HSCs, we compared the effects of overexpression of p-Pten and nonphosphorylated Pten (non-p-Pten) on the hematopoietic reconstitutive capacity (HRC) of HSCs. We found that overexpression of non-p-Pten enhances the LT-HRC of HSCs, whereas overexpression of p-Pten promotes myeloid differentiation and compromises the LT-HRC of HSCs. Such phosphorylation-regulated Pten functioning is mediated by repressing the cell:cell contact-induced activation of Fak/p38 signaling independent of Pten's lipid phosphatase activity because both p-Pten and non-p-Pten have comparable activity in repressing PI3K/Akt signaling. Our studies suggest that, in addition to repressing PI3K/Akt/mTor signaling, non-p-Pten maintains HSCs in bone marrow niches via a cell-contact inhibitory mechanism by inhibiting Fak/p38 signaling-mediated proliferation and differentiation. In contrast, p-Pten promotes the proliferation and differentiation of HSCs by enhancing the cell contact-dependent activation of Src/Fak/p38 signaling. Stem Cells 2016;34:2130-2144.
磷酸化形式的Pten（p-Pten）在超过70%的急性髓系白血病样本中高表达。然而，p-Pten在正常和异常造血过程中的作用尚未得到研究。我们发现，长期（LT）造血干细胞（HSC）、短期（ST）HSC和多能祖细胞（MPP）中的Pten蛋白水平相当；然而，在HSC向MPP转变过程中，p-Pten的水平会升高。为了研究p-Pten是否参与调节HSC的自我更新和分化，我们比较了p-Pten和非磷酸化Pten（非p-Pten）过表达对HSC造血重建能力（HRC）的影响。我们发现，非p-Pten的过表达增强了HSC的LT-HRC，而p-Pten的过表达促进了髓系分化并损害了HSC的LT-HRC。这种磷酸化调节的Pten功能是通过抑制细胞间接触诱导的Fak/p38信号激活来介导的，这与Pten的脂质磷酸酶活性无关，因为p-Pten和非p-Pten在抑制PI3K/Akt信号方面具有相当的活性。我们的研究表明，除了抑制PI3K/Akt/mTor信号外，非p-Pten还通过抑制Fak/p38信号介导的增殖和分化，通过细胞接触抑制机制将HSC维持在骨髓龛中。相比之下，p-Pten通过增强Src/Fak/p38信号的细胞接触依赖性激活来促进HSC的增殖和分化。《干细胞》2016年；34:2130 - 2144。
