Adaptor proteins NUMB and NUMBL promote cell cycle withdrawal by targeting ERBB2 for degradation
Adaptor proteins NUMB and NUMBL promote cell cycle withdrawal by targeting ERBB2 for degradation
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DOI：
10.1172/jci91081
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发表时间：
2017-02-01
影响因子：
15.9
通讯作者：
Evans, Sylvia M.
中科院分区：
文献类型：
--
作者：
Hirai, Maretoshi;Arita, Yoh;Evans, Sylvia M.
小梁肌细胞不能进行适当的细胞周期退出导致心室致密化不全和心力衰竭。生长因子受体ERBB2的信号传导对于肌细胞增殖和小梁形成至关重要。然而，小梁ERBB2信号转导的适当下调的潜在机制知之甚少。在这里，我们发现，内吞衔接蛋白NUMB和NUMBL需要在成熟的小梁ERBB2信号的下调。NUMB和NUMBL的缺失导致晚期内体形成的部分阻断，导致持续的ERBB2信号传导和STAT5活化。出乎意料的是，激活的STAT5推翻了Hippo介导的抑制，并将YAP 1驱动到细胞核。伴随的异常心肌细胞增殖导致心室致密化不全，ERBB 2或YAP 1的杂合性功能丧失显著挽救了心室致密化不全。进一步的研究表明，NUMB和NUMBL与小GT受体Rab7相互作用，将ERBB 2从早期内体转移到晚期内体进行降解。我们的研究提供了深入了解NUMB和NUMBL促进心肌细胞细胞周期退出的机制，并强调了心肌细胞细胞周期重入的重要途径之间先前未被怀疑的联系，与心室致密化不全心肌病和再生医学相关。
Failure of trabecular myocytes to undergo appropriate cell cycle withdrawal leads to ventricular noncompaction and heart failure. Signaling of growth factor receptor ERBB2 is critical for myocyte proliferation and trabeculation. However, the mechanisms underlying appropriate downregulation of trabecular ERBB2 signaling are little understood. Here, we have found that the endocytic adaptor proteins NUMB and NUMBL were required for downregulation of ERBB2 signaling in maturing trabeculae. Loss of NUMB and NUMBL resulted in a partial block of late endosome formation, resulting in sustained ERBB2 signaling and STAT5 activation. Unexpectedly, activated STAT5 overrode Hippo-mediated inhibition and drove YAP1 to the nucleus. Consequent aberrant cardiomyocyte proliferation resulted in ventricular noncompaction that was markedly rescued by heterozygous loss of function of either ERBB2 or YAP1. Further investigations revealed that NUMB and NUMBL interacted with small GTPase Rab7 to transition ERBB2 from early to late endosome for degradation. Our studies provide insight into mechanisms by which NUMB and NUMBL promote cardiomyocyte cell cycle withdrawal and highlight previously unsuspected connections between pathways that are important for cardiomyocyte cell cycle reentry, with relevance to ventricular noncompaction cardiomyopathy and regenerative medicine.