The Src homology 2 protein Shb promotes cell cycle progression in murine hematopoietic stem cells by regulation of focal adhesion kinase activity
The Src homology 2 protein Shb promotes cell cycle progression in murine hematopoietic stem cells by regulation of focal adhesion kinase activity
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DOI：
10.1016/j.yexcr.2013.03.020
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发表时间：
2013-07-15
影响因子：
3.7
通讯作者：
Welsh, Michael
中科院分区：
文献类型：
--
作者：
Gustafsson, Karin;Heffner, Garrett;Welsh, Michael
广泛表达的衔接蛋白Shb先前已被报道有助于T细胞功能，由于其与T细胞受体的关联，此外，Shb的几种已知的相互作用伴侣是血细胞发育和功能的既定调节剂。此外，Shb缺陷型胚胎干细胞在体外分化时显示血细胞集落形成减少。因此，本研究的目的是探讨Shb基因敲除小鼠的造血干细胞和祖细胞功能。Shb缺陷型骨髓含有相对数量减少的长期造血干细胞（LT-HSC），表现出较低的增殖率。尽管如此，Shb敲除LT-HSC通过响应于5-氟尿嘧啶处理的遗传毒性应激而进入细胞周期来迅速响应。在竞争性LT-HSC移植中，Shb无效细胞最初与野生型细胞一样移植，但随着时间的推移提供较少的骨髓扩增。此外，Shb基因敲除的骨髓细胞表现出粘着斑激酶/Rac 1/p21激活激酶信号传导的基础活性升高，对干细胞因子刺激的反应性降低。因此，用粘着斑激酶抑制剂治疗增加Shb敲除LT-HSC增殖。因此，改变的信号特征为LT-HSC增殖的变化提供了一个合理的机制解释，因为这些信号中间体都已被证明参与LT-HSC细胞周期控制。总之，骨髓细胞中Shb依赖性信号传导的丧失，导致稳态造血下LT-HSC中粘着斑激酶活性升高和增殖反应降低，对LT-HSC随时间的维持不利。(C)版权所有© 2013 Elsevier Inc.
The widely expressed adaptor protein Shb has previously been reported to contribute to T cell function due to its association with the T cell receptor and furthermore, several of Shb's known interaction partners are established regulators of blood cell development and function. In addition, Shb deficient embryonic stem cells displayed reduced blood cell colony formation upon differentiation in vitro. The aim of the current study was therefore to explore hematopoietic stem and progenitor cell function in the Shb knockout mouse. Shb deficient bone marrow contained reduced relative numbers of long-term hematopoietic stem cells (LT-HSCs) that exhibited lower proliferation rates. Despite this, Shb knockout LT-HSCs responded promptly by entering the cell cycle in response to genotoxic stress by 5-fluorouracil treatment In competitive LT-HSC transplantations, Shb null cells initially engrafted as well as the wildtype cells but provided less myeloid expansion over time. Moreover, Shb knockout bone marrow cells exhibited elevated basal activities of focal adhesion kinase/Rac1/p21-activated kinase signaling and reduced responsiveness to Stem Cell Factor stimulation. Consequently, treatment with a focal adhesion kinase inhibitor increased Shb knockout LT-HSC proliferation. The altered signaling characteristics thus provide a plausible mechanistic explanation for the changes in LT-HSC proliferation since these signaling intermediates have all been shown to participate in LT-HSC cell cycle control. In summary, the loss of Shb dependent signaling in bone marrow cells, resulting in elevated focal adhesion kinase activity and reduced proliferative responses in LT-HSCs under steady state hematopoiesis, confers a disadvantage to the maintenance of LT-HSCs over time. (C) 2013 Elsevier Inc All rights reserved.