Jiang T, Pan C Q, Low B C
Department of Biological Sciences, National University of Singapore, Singapore.
Mechanobiology Institute, National University of Singapore, Singapore.
Oncogene. 2017 Jun 1;36(22):3178-3192. doi: 10.1038/onc.2016.466. Epub 2017 Jan 16.
Simultaneous hyperactivation of stress-activated protein kinase/c-Jun N-terminal protein kinase (SAPK/JNK) and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) signaling cascades has been reported in carcinogenesis. However, how they are integrated to promote oncogenesis remains unknown. By analyzing breast invasive carcinoma database (The Cancer Genome Altas), we found that the mRNA expression levels of both JNK1 and ERK2 are positively correlated with the mRNA level of EEA1, an endosome associated protein, indicating the potential JNK/ERK crosstalk at endosome. Unbiased screen of different endosome-associated Rab GTPases reveals that late endosome serves as a unique platform to integrate JNK/ERK signaling. Furthermore, we identify that BPGAP1 (a BCH domain-containing, Cdc42GAP-like Rho GTPase-activating protein) promotes MEK partner 1 (MP1)-induced ERK activation on late endosome through scaffolding MP1/MEK1 complex. This regulatory function requires phosphorylation of BPGAP1 by JNK at its C terminal tail (Ser424) to unlock its autoinhibitory conformation. Consequently, phosphorylated BPGAP1 facilitates endosomal ERK signaling transduction to the nucleus, driving cell proliferation and transformation via the ERK-Myc-CyclinA axis. BPGAP1 therefore provides a crucial spatiotemporal checkpoint where JNK and MP1/MEK1 work in concert to regulate endosomal and nuclear ERK signaling in cell proliferation control.
在癌症发生过程中，应激激活蛋白激酶/c-Jun氨基末端蛋白激酶（SAPK/JNK）和丝裂原活化蛋白激酶激酶/细胞外信号调节激酶（MEK/ERK）信号级联的同时过度激活已有报道。然而，它们如何整合以促进肿瘤发生仍不清楚。通过分析乳腺浸润性癌数据库（癌症基因组图谱），我们发现JNK1和ERK2的mRNA表达水平均与一种内体相关蛋白EEA1的mRNA水平呈正相关，这表明内体处存在潜在的JNK/ERK串扰。对不同内体相关Rab GTP酶的无偏筛选表明，晚期内体是整合JNK/ERK信号的独特平台。此外，我们发现BPGAP1（一种含BCH结构域、Cdc42GAP样Rho GTP酶激活蛋白）通过搭建MP1/MEK1复合物促进晚期内体上MEK伴侣1（MP1）诱导的ERK激活。这种调节功能需要JNK在BPGAP1的C末端尾巴（Ser424）处将其磷酸化以解锁其自身抑制构象。因此，磷酸化的BPGAP1促进内体ERK信号转导至细胞核，通过ERK-Myc-细胞周期蛋白A轴驱动细胞增殖和转化。因此，BPGAP1提供了一个关键的时空检查点，在该点JNK和MP1/MEK1协同作用以调节细胞增殖控制中的内体和核ERK信号。
