MAGI-3 与 NHERF-2 竞争，负调控结肠癌细胞中 LPA2 受体信号。
MAGI-3 competes with NHERF-2 to negatively regulate LPA2 receptor signaling in colon cancer cells.
机构信息
Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
出版信息
Gastroenterology. 2011 Mar;140(3):924-34. doi: 10.1053/j.gastro.2010.11.054. Epub 2010 Dec 4.
BACKGROUND & AIMS: Lysophosphatidic acid (LPA) is a potent inducer of colon cancer and LPA receptor type 2 (LPA(2)) is overexpressed in colon tumors. LPA(2) 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 LPA(2)-mediated signaling in human colon cancer cells.
METHODS
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 nuclear factor-κB activation were determined. Expression of MAGI-3 and NHERF-2 in human colon tumor tissues was analyzed using tissue microarray analysis.
RESULTS
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 LPA(2) and phospholipase C-β3. However, NHERF-2 and MAGI-3 reciprocally regulated LPA(2)-induced phospholipase C activity. MAGI-3 increased the interaction of LPA(2) with Gα(12), whereas NHERF-2 preferentially promoted interaction between LPA(2) and Gα(q). MAGI-3 decreased the tumorigenic capacity of LPA(2) by attenuating the activities of nuclear factor-κB and c-Jun N-terminal kinase. MAGI-3 and NHERF-2 were expressed differentially in colon adenocarcinomas, consistent with their opposing effects.
CONCLUSIONS
LPA(2) is dynamically regulated by 2 distinct PDZ proteins via modulation of G-protein coupling and receptor signaling. MAGI-3 is a negative regulator of LPA(2) signaling.
背景与目的
溶血磷脂酸（LPA）是结肠癌的有效诱导物，LPA 受体 2（LPA2）在结肠癌肿瘤中过表达。LPA2 与膜相关鸟苷酸激酶反向定向 3（MAGI-3）和钠离子/氢离子交换调节因子 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 在人结肠癌细胞中 LPA2 介导的信号传导中的作用。
方法
我们在 HCT116 和 SW480 细胞中转染 MAGI-3 过表达或敲低。通过检测细胞迁移、侵袭、肌醇磷酸盐生成和核因子-κB 激活，研究 MAGI-3 和 NHERF-2 在 LPA 诱导的信号转导中的作用。使用组织微阵列分析检测人结肠癌组织中 MAGI-3 和 NHERF-2 的表达。
结果
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 竞争与 LPA2 和磷脂酶 C-β3 结合。然而，NHERF-2 和 MAGI-3 相互调节 LPA2 诱导的磷脂酶 C 活性。MAGI-3 增加了 LPA2 与 Gα12 的相互作用，而 NHERF-2 则优先促进 LPA2 与 Gαq 的相互作用。MAGI-3 通过减弱核因子-κB 和 c-Jun N 端激酶的活性，降低了 LPA2 的致瘤能力。MAGI-3 和 NHERF-2 在结肠癌腺癌中的表达存在差异，与它们的拮抗作用一致。
结论
LPA2 通过调节 G 蛋白偶联和受体信号，被 2 种不同的 PDZ 蛋白动态调节。MAGI-3 是 LPA2 信号的负调节剂。
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