ERK5 signalling rescues intestinal epithelial turnover and tumour cell proliferation upon ERK1/2 abrogation.
ERK5 signalling rescues intestinal epithelial turnover and tumour cell proliferation upon ERK1/2 abrogation.
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DOI：
10.1038/ncomms11551
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发表时间：
2016-05-17
影响因子：
16.6
通讯作者：
Raz E
中科院分区：
文献类型：
--
作者：
de Jong PR;Taniguchi K;Harris AR;Bertin S;Takahashi N;Duong J;Campos AD;Powis G;Corr M;Karin M;Raz E
ERK1/2 MAPK信号模块整合了诱导上皮谱系增殖和分化的细胞外信号，是一种确定的致癌驱动因素，特别是在肠道中。然而，在肠上皮细胞和结直肠癌（CRC）中，ERK1/2模块与其他信号通路的相互关系尚不清楚。本研究表明，肠上皮细胞中Erk1/2的缺失会导致营养吸收、上皮细胞迁移和分泌细胞分化的缺陷。然而，肠上皮细胞增殖不受阻碍，暗示代偿机制。Erk1/2的遗传缺失或MEK1/2的药理靶向导致ERK5通路的超生理活性。此外，靶向这两种途径可以更有效地抑制小鼠肠道类器官和人类CRC细胞系的细胞增殖。这些结果表明，ERK5在肠上皮细胞中提供了一个共同的旁路通路，在ERK1/2信号通路被破坏后恢复细胞增殖，具有治疗CRC的意义。目前尚不清楚细胞外信号调节激酶1和2 （ERK1/2）通路如何与肠上皮细胞中的其他信号相互作用。在这里，作者表明，当Erk1/2缺失或MEK1/2的药理抑制时，ERK5通路上调以维持上皮细胞增殖。
The ERK1/2 MAPK signalling module integrates extracellular cues that induce proliferation and differentiation of epithelial lineages, and is an established oncogenic driver, particularly in the intestine. However, the interrelation of the ERK1/2 module relative to other signalling pathways in intestinal epithelial cells and colorectal cancer (CRC) is unclear. Here we show that loss of Erk1/2 in intestinal epithelial cells results in defects in nutrient absorption, epithelial cell migration and secretory cell differentiation. However, intestinal epithelial cell proliferation is not impeded, implying compensatory mechanisms. Genetic deletion of Erk1/2 or pharmacological targeting of MEK1/2 results in supraphysiological activity of the ERK5 pathway. Furthermore, targeting both pathways causes a more effective suppression of cell proliferation in murine intestinal organoids and human CRC lines. These results suggest that ERK5 provides a common bypass route in intestinal epithelial cells, which rescues cell proliferation upon abrogation of ERK1/2 signalling, with therapeutic implications in CRC. It is unclear how the extracellular signal-regulated kinases 1 and 2 (ERK1/2) pathways interact with other signals in intestinal epithelial cells. Here, the authors show that upon loss of Erk1/2, or pharmacological inhibition of MEK1/2, the ERK5 pathway is upregulated to maintain epithelial cell proliferation.