Balasooriya Gayan I, Johnson Jo-Anne, Basson M Albert, Rawlins Emma L
Wellcome Trust/CRUK Gurdon Institute, Wellcome Trust/MRC Stem Cell Institute, Department of Pathology, University of Cambridge, Cambridge CB2 1QN, UK.
Department of Craniofacial Development and Stem Cell Biology, King's College London, London SE1 9RT, UK.
Dev Cell. 2016 Apr 4;37(1):85-97. doi: 10.1016/j.devcel.2016.03.001.
The steady-state airway epithelium has a low rate of stem cell turnover but can nevertheless mount a rapid proliferative response following injury. This suggests a mechanism to restrain proliferation at steady state. One such mechanism has been identified in skeletal muscle in which pro-proliferative FGFR1 signaling is antagonized by SPRY1 to maintain satellite cell quiescence. Surprisingly, we found that deletion of Fgfr1 or Spry2 in basal cells of the adult mouse trachea caused an increase in steady-state proliferation. We show that in airway basal cells, SPRY2 is post-translationally modified in response to FGFR1 signaling. This allows SPRY2 to inhibit intracellular signaling downstream of other receptor tyrosine kinases and restrain basal cell proliferation. An FGFR1-SPRY2 signaling axis has previously been characterized in cell lines in vitro. We now demonstrate an in vivo biological function of this interaction and thus identify an active signaling mechanism that maintains quiescence in the airway epithelium.
稳态气道上皮的干细胞更新率较低，但在损伤后仍能迅速产生增殖反应。这表明存在一种在稳态时抑制增殖的机制。在骨骼肌中已发现一种这样的机制，即促增殖的FGFR1信号被SPRY1拮抗，以维持卫星细胞的静止状态。令人惊讶的是，我们发现成年小鼠气管基底细胞中Fgfr1或Spry2的缺失导致稳态增殖增加。我们表明，在气道基底细胞中，SPRY2会响应FGFR1信号进行翻译后修饰。这使得SPRY2能够抑制其他受体酪氨酸激酶下游的细胞内信号传导，并抑制基底细胞增殖。FGFR1-SPRY2信号轴此前已在体外细胞系中得到表征。我们现在证明了这种相互作用在体内的生物学功能，从而确定了一种维持气道上皮静止状态的活跃信号机制。
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