MAGI-3 competes with NHERF-2 to negatively regulate LPA2 receptor signaling in colon cancer cells.
MAGI-3 competes with NHERF-2 to negatively regulate LPA2 receptor signaling in colon cancer cells.
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DOI：
10.1053/j.gastro.2010.11.054
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发表时间：
2011-03
期刊：
影响因子：
29.4
通讯作者：
Yun CC
中科院分区：
文献类型：
--
作者：
Lee SJ;Ritter SL;Zhang H;Shim H;Hall RA;Yun CC
溶血磷脂酸(LPA)是结肠癌的有效诱导物，LPA受体2型(LPA2)在结肠癌中高表达。LPA2与膜相关的反向鸟苷酸激酶(MAGI-3)和Na+/H+交换调节因子2(NHERF-2)相互作用，但这些相互作用的生物学效应尚不清楚。我们研究了MAGI-3和NHERF-2在LPA2介导的人结肠癌细胞信号转导中的作用。我们在HCT116和SW480细胞中过表达或敲除了MAGI-3。检测MAGI3和NHERF2在LPA诱导的细胞迁移、侵袭、肌醇磷酸生成和NF-κB激活中的作用。应用组织芯片技术分析MAGI-3和NHERF-2在人结肠癌组织中的表达。NHERF-2促进结肠癌细胞的迁移和侵袭，而MAGI-3则抑制这些过程。MAGI-3与NHERF-2竞争结合LPA2和磷脂酶C(PLC)-β3，而NHERF-2和MAGI-3相互调节LPA2诱导的PLC活性。MAGI-3增强LPA2与Gα12的相互作用，NHERF-2优先促进LPA2与GαQ之间的相互作用，MAGI-3通过抑制NF-κB和c-jun氨基末端激酶的活性而降低LPA2的致瘤能力。MAGI-3和NHERF-2在结肠腺癌中有不同的表达，这与它们的相反作用一致。LPA2受两种不同的PDZ蛋白通过G蛋白偶联和受体信号的调节而动态调节。MAGI-3是LPA2信号的负调控因子。
Lysophosphatidic acid (LPA) is a potent inducer of colon cancer and LPA receptor type 2 (LPA2) is overexpressed in colon tumors. LPA2 interacts with membrane-associated guanylate kinase with inverted orientation-3 (MAGI-3) and the Na+/H+ exchanger regulatory factor 2 (NHERF-2), but the biological effects of these interactions are unknown. We investigated the roles of MAGI-3 and NHERF-2 in LPA2-mediated signaling in human colon cancer cells. We overexpressed or knocked down MAGI-3 in HCT116 and SW480 cells. The effects of MAGI-3 and NHERF-2 in LPA-induced cell migration, invasion, inositol phosphate generation, and NF-κB activation were determined. Expression of MAGI-3 and NHERF-2 in human colon tumor tissues was analyzed using tissue microarray analysis. NHERF-2 promoted migration and invasion of colon cancer cells, whereas MAGI-3 inhibited these processes. MAGI-3 competed with NHERF-2 for binding to LPA2 and phospholipase C (PLC)-β3. However, NHERF-2 and MAGI-3 reciprocally regulated LPA2-induced PLC activity. MAGI-3 increased the interaction of LPA2 with Gα12, whereas NHERF-2 preferentially promoted interaction between LPA2 and Gαq. MAGI-3 decreased the tumorigenic capacity of LPA2 by attenuating the activities of NF-κB and c-Jun N-terminal kinase. MAGI-3 and NHERF-2 were differentially expressed in colon adenocarcinomas, consistent with their opposing effects. LPA2 is dynamically regulated by 2 distinct PDZ proteins via modulation of G protein coupling and receptor signaling. MAGI-3 is a negative regulator of LPA2 signaling.
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影响因子：
29.4
作者：
Lin S;Wang D;Iyer S;Ghaleb AM;Shim H;Yang VW;Chun J;Yun CC
通讯作者：
Yun CC
影响因子：
64.5
作者：
Nomura DK;Long JZ;Niessen S;Hoover HS;Ng SW;Cravatt BF
通讯作者：
Cravatt BF
影响因子：
8.8
作者：
通讯作者：
--
DOI：
10.1152/ajpgi.00321.2010
发表时间：
2010-11-01
影响因子：
4.5
作者：
Lin, Songbai;Lee, Sei-Jung;Yun, C. Chris
通讯作者：
Yun, C. Chris
DOI：
10.1016/j.bbagen.2007.04.008
发表时间：
2007-08-01
影响因子：
3
作者：
Rusovici, Raluca;Ghaleb, Amr;Yun, C. Chris
通讯作者：
Yun, C. Chris