Ji Haitao, Wang Ji, Nika Heinz, Hawke David, Keezer Susan, Ge Qingyuan, Fang Bingliang, Fang Xuexun, Fang Dexing, Litchfield David W, Aldape Kenneth, Lu Zhimin
Brain Tumor Center and Department of Neuro-Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, 77030, USA.
Mol Cell. 2009 Nov 25;36(4):547-59. doi: 10.1016/j.molcel.2009.09.034.
Increased transcriptional activity of beta-catenin resulting from Wnt/Wingless-dependent or -independent signaling has been detected in many types of human cancer, but the underlying mechanism of Wnt-independent regulation remains unclear. We demonstrate here that EGFR activation results in disruption of the complex of beta-catenin and alpha-catenin, thereby abrogating the inhibitory effect of alpha-catenin on beta-catenin transactivation via CK2alpha-dependent phosphorylation of alpha-catenin at S641. ERK2, which is activated by EGFR signaling, directly binds to CK2alpha via the ERK2 docking groove and phosphorylates CK2alpha primarily at T360/S362, subsequently enhancing CK2alpha activity toward alpha-catenin phosphorylation. In addition, levels of alpha-catenin S641 phosphorylation correlate with levels of ERK1/2 activity in human glioblastoma specimens and with grades of glioma malignancy. This EGFR-ERK-CK2-mediated phosphorylation of alpha-catenin promotes beta-catenin transactivation and tumor cell invasion. These findings highlight the importance of the crosstalk between EGFR and Wnt pathways in tumor development.
在许多类型的人类癌症中均检测到,由Wnt/Wingless依赖性或非依赖性信号传导导致的β-连环蛋白转录活性增加,但Wnt非依赖性调节的潜在机制仍不清楚。我们在此证明,表皮生长因子受体(EGFR)激活会导致β-连环蛋白与α-连环蛋白复合物的破坏,从而消除α-连环蛋白通过在S641位点对α-连环蛋白进行CK2α依赖性磷酸化而对β-连环蛋白反式激活的抑制作用。由EGFR信号传导激活的细胞外信号调节激酶2(ERK2)通过ERK2对接槽直接与CK2α结合,并主要在T360/S362位点磷酸化CK2α,随后增强CK2α对α-连环蛋白磷酸化的活性。此外,在人类胶质母细胞瘤标本中,α-连环蛋白S641位点的磷酸化水平与ERK1/2活性水平以及胶质瘤恶性程度相关。这种由EGFR-ERK-CK2介导的α-连环蛋白磷酸化促进了β-连环蛋白的反式激活和肿瘤细胞侵袭。这些发现突出了EGFR与Wnt信号通路之间的串扰在肿瘤发展中的重要性。