Hematopoietic Stem Cell Activity Is Regulated by Pten Phosphorylation Through a Niche-Dependent Mechanism.
Hematopoietic Stem Cell Activity Is Regulated by Pten Phosphorylation Through a Niche-Dependent Mechanism.
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Pten 磷酸化通过生态位依赖性机制调节造血干细胞活性。
DOI：
10.1002/stem.2382
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发表时间：
2016
期刊：
影响因子：
5.2
通讯作者：
Zhang Jiwang
中科院分区：
文献类型：
--
作者：
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
Pten的磷酸化形式（p-Pten）在>70%的急性髓性白血病样品中高度表达。然而，p-Pten在正常和异常造血中的作用尚未研究。我们发现Pten蛋白水平在长期（LT）造血干细胞（HSC）、短期（ST）HSC和多能祖细胞（MPP）之间是相当的;然而，在HSC向MPP转变期间p-Pten水平升高。为了研究p-Pten是否参与调控HSC的自我更新和分化，我们比较了p-Pten和非磷酸化Pten（non-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HSC的髓样分化并损害了HSC的LT-HRC。这种磷酸化调节的Pten功能是通过抑制细胞：细胞接触诱导的Fak/p38信号传导的激活介导的，而不依赖于Pten的脂质磷酸酶活性，因为p-Pten和非p-Pten在抑制PI 3 K/Akt信号传导方面具有相当的活性。我们的研究表明，除了抑制PI 3 K/Akt/mTor信号传导外，non-p-Pten通过细胞接触抑制机制通过抑制Fak/p38信号传导介导的增殖和分化来维持HSC在骨髓小生境中。相反，p-Pten通过增强Src/Fak/p38信号传导的细胞接触依赖性激活来促进HSC的增殖和分化。
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.