The CalcR-PKA-Yap1 Axis Is Critical for Maintaining Quiescence in Muscle Stem Cells.
The CalcR-PKA-Yap1 Axis Is Critical for Maintaining Quiescence in Muscle Stem Cells.
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DOI：
10.1016/j.celrep.2019.10.057
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发表时间：
2019-11
期刊：
影响因子：
8.8
通讯作者：
Lidan Zhang;Yu-taro Noguchi;H. Nakayama;Takayuki Kaji;K. Tsujikawa;M. Ikemoto-Uezumi;A. Uezumi;Yoshiaki Okada;T. Doi;Shuichi Watanabe;T. Braun;Y. Fujio;S. Fukada
中科院分区：
文献类型：
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作者：
Lidan Zhang;Yu-taro Noguchi;H. Nakayama;Takayuki Kaji;K. Tsujikawa;M. Ikemoto-Uezumi;A. Uezumi;Yoshiaki Okada;T. Doi;Shuichi Watanabe;T. Braun;Y. Fujio;S. Fukada
静止是成体干细胞的基本特性。最近的证据表明，静止不是一种默认状态，但需要主动信号来防止干细胞意外或过早激活。降钙素受体(CalcR)对维持肌肉卫星(干细胞)细胞(MuSCs)的静止至关重要。然而，CalcR信号调节MUSCs静止的分子机制仍然是个谜。在这里，我们证明了蛋白激酶A催化结构域(PKA)的转基因表达恢复了CalcR突变的MUSCs的静止，并延迟了MUSC的激活。在机制上，CalcR激活的PKA使Hippo信号的主要效应者Lats1/2磷酸化，从而抑制YAP1的核积累，从而阻止Hippo靶基因的表达，包括细胞周期相关分子。重要的是，在CalcR突变的MuSCs中，YAP1的基因失活恢复了CalcR突变的MuSCs的静止，表明CalcR-PKA-Lats1/2-YAP1轴在维持MUSC的静止中起着关键作用。
Quiescence is a fundamental property of adult stem cells. Recent evidence indicates that quiescence is not a default state but requires active signaling that prevents accidental or untimely activation of stem cells. The calcitonin receptor (CalcR) is critical for sustaining quiescence in muscle satellite (stem) cells (MuSCs). However, the molecular mechanisms by which CalcR signaling regulates quiescence in MuSCs are enigmatic. Here, we demonstrate that transgenic expression of the catalytic domain of protein kinase A (PKA) restores the quiescence of CalcR-mutant MuSCs and delays MuSC activation. Mechanistically, CalcR-activated PKA phosphorylates Lats1/2, the main effector of Hippo signaling, thereby inhibiting the nuclear accumulation of Yap1, which prevents expression of Hippo-target genes, including cell-cycle-related molecules. Importantly, genetic inactivation of Yap1 in CalcR-mutant MuSCs reinstates quiescence in CalcR-mutant MuSCs, indicating that the CalcR-PKA-Lats1/2-Yap1 axis plays a critical role in sustaining MuSC quiescence.