Yan J, Yang Y, Zhang H, King C, Kan H-M, Cai Y, Yuan C-X, Bloom G S, Hua X
Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Oncogene. 2009 Feb 19;28(7):973-82. doi: 10.1038/onc.2008.435. Epub 2008 Dec 15.
Multiple endocrine neoplasia type 1 (MEN1) is a dominantly inherited tumor syndrome that results from the mutation of the MEN1 gene that encodes protein menin. Stable overexpression of MEN1 has been shown to partially suppress the Ras-mediated morphological changes of fibroblast cells. Little is known about the molecular mechanisms by which menin decreases the oncogenic effects on cell morphology and other phenotypes. Here we showed that ectopic expression of menin in pretumor beta-cells increases islet cell adhesion and reduces cell migration. Our further studies revealed that menin interacts with the scaffold protein, IQ motif containing GTPase activating protein 1 (IQGAP1), reduces GTP-Rac1 interaction with IQGAP1 but increases epithelial cadherin (E-cadherin)/beta-catenin interaction with IQGAP1. Consistent with an essential role for menin in regulating beta-cell adhesion in vivo, accumulations of beta-catenin and E-cadherin are reduced at cell junctions in the islets from Men1-excised mice. Together, these results define a novel menin-IQGAP1 pathway that controls cell migration and cell-cell adhesion in endocrine cells.
1型多发性内分泌肿瘤（MEN1）是一种显性遗传肿瘤综合征，由编码蛋白menin的MEN1基因突变引起。MEN1的稳定过表达已被证明可部分抑制Ras介导的成纤维细胞形态变化。关于menin降低对细胞形态和其他表型致癌作用的分子机制知之甚少。在这里，我们表明，在肿瘤前β细胞中异位表达menin可增加胰岛细胞黏附并减少细胞迁移。我们的进一步研究表明，menin与支架蛋白含IQ模体的GTP酶激活蛋白1（IQGAP1）相互作用，减少GTP-Rac1与IQGAP1的相互作用，但增加上皮钙黏蛋白（E-cadherin）/β-连环蛋白与IQGAP1的相互作用。与menin在体内调节β细胞黏附中的重要作用一致，在切除Men1的小鼠胰岛的细胞连接处，β-连环蛋白和E-cadherin的积累减少。总之，这些结果定义了一条新的menin-IQGAP1途径，该途径控制内分泌细胞中的细胞迁移和细胞间黏附。
