Giles Amber J, Bender Timothy P, Ravichandran Kodi S
Carter Immunology Center and Department of Microbiology, University of Virginia, Charlottesville, VA 22908, USA.
J Immunol. 2009 Nov 1;183(9):5468-76. doi: 10.4049/jimmunol.0902344. Epub 2009 Oct 14.
The adaptor protein Shc is phosphorylated downstream of many cell surface receptors, including Ag and cytokine receptors. However, the role of Shc in B cell development has not been addressed. Here, through conditional expression of a dominant negative Shc mutant and conditional loss of Shc protein expression, we tested a role for Shc during early B lymphopoiesis. We identified a requirement for Shc beginning at the transition from the pre-pro-B to pro-B stage, with a strong reduction in the number of pre-B cells. This developmental defect is due to increased cell death rather than impaired proliferation or commitment to the B lineage. Additional studies suggest a role for Shc in IL-7-dependent signaling in pro-B cells. Shc is phosphorylated in response to IL-7 stimulation in pro-B cells, and pro-B cells from mice with impaired Shc signaling display increased apoptosis. Together, these data demonstrate a critical role for Shc in early B lymphopoiesis with a requirement in early B cell survival. In addition, we also identify Shc as a required player in signaling downstream of the IL-7R in early B cells.
衔接蛋白Shc在包括抗原和细胞因子受体在内的许多细胞表面受体下游被磷酸化。然而，Shc在B细胞发育中的作用尚未得到研究。在这里，通过条件性表达显性负性Shc突变体和条件性缺失Shc蛋白表达，我们测试了Shc在早期B淋巴细胞生成过程中的作用。我们发现从pre-pro-B细胞向pro-B细胞转变时就需要Shc，前B细胞数量大幅减少。这种发育缺陷是由于细胞死亡增加，而非增殖受损或向B细胞系的定向分化受损。进一步的研究表明Shc在pro-B细胞中依赖白细胞介素-7的信号传导中发挥作用。在pro-B细胞中，Shc会因白细胞介素-7刺激而被磷酸化，并且Shc信号传导受损的小鼠的pro-B细胞显示出凋亡增加。总之，这些数据证明了Shc在早期B淋巴细胞生成中起着关键作用，对早期B细胞存活是必需的。此外，我们还确定Shc是早期B细胞中白细胞介素-7受体下游信号传导的必需参与者。
