Lou Xiaomin, Kang Bin, Zhang Jun, Hao Chunyi, Tian Xiuyun, Li Wenmei, Xu Ningzhi, Lu Youyong, Liu Siqi
CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, No. 1 Beichen West Road, Chaoyang District, Beijing 100101, China.
Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research, Peking University School of Oncology, Beijing Institute for Cancer Research, 52 Fucheng Road, Haidian District, Beijing 100142, China.
Biochim Biophys Acta. 2014 Sep;1842(9):1423-32. doi: 10.1016/j.bbadis.2014.04.006. Epub 2014 Apr 13.
An abundance of microfibril-associated glycoprotein 3-like (MFAP3L) significantly correlates with distant metastasis in colorectal cancer (CRC), although the mechanism has yet to be explained. In this study, we observed that MFAP3L knock-down resulted in reduced CRC cell invasion and hepatic metastasis. We evaluated the cellular location and biochemical functions of MFAP3L and found that this protein was primarily localized in the nucleus of CRC cells and acted as a protein kinase. When EGFR translocated into the nucleus upon stimulation with EGF, MFAP3L was phosphorylated at Tyr287 within its SH2 motif, and the activated form of MFAP3L phosphorylated ERK2 at Thr185 and Tyr187. Moreover, the metastatic behavior of CRC cells in vitro and in vivo could be partially explained by activation of the nuclear ERK pathway through MFAP3L phosphorylation. Hence, we experimentally demonstrated for the first time that MFAP3L likely participates in the nuclear signaling of EGFR and ERK2 and acts as a novel nuclear kinase that impacts CRC metastasis.
大量的微原纤维相关糖蛋白3样蛋白（MFAP3L）与结直肠癌（CRC）的远处转移显著相关，尽管其机制尚待阐明。在本研究中，我们观察到敲低MFAP3L会导致CRC细胞侵袭和肝转移减少。我们评估了MFAP3L的细胞定位和生化功能，发现该蛋白主要定位于CRC细胞核中，并作为一种蛋白激酶发挥作用。当表皮生长因子（EGF）刺激导致表皮生长因子受体（EGFR）转位到细胞核时，MFAP3L在其SH2基序内的酪氨酸287位点被磷酸化，而活化形式的MFAP3L则在苏氨酸185和酪氨酸187位点磷酸化细胞外信号调节激酶2（ERK2）。此外，CRC细胞在体外和体内的转移行为可以部分通过MFAP3L磷酸化激活核ERK途径来解释。因此，我们首次通过实验证明，MFAP3L可能参与EGFR和ERK2的核信号传导，并作为一种影响CRC转移的新型核激酶发挥作用。
