Integrin-binding Protein Nischarin Interacts with Tumor Suppressor Liver Kinase B1 (LKB1) to Regulate Cell Migration of Breast Epithelial Cells
Integrin-binding Protein Nischarin Interacts with Tumor Suppressor Liver Kinase B1 (LKB1) to Regulate Cell Migration of Breast Epithelial Cells
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DOI：
10.1074/jbc.m112.418103
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发表时间：
2013-05-31
影响因子：
4.8
通讯作者：
Alahari, Suresh K.
中科院分区：
文献类型：
--
作者：
Jain, Prachi;Baranwal, Somesh;Alahari, Suresh K.
LKB1是一种丝氨酸/苏氨酸激酶，在30%的肺腺癌中被检测到双等位基因失活，并显示出抑制乳腺肿瘤生长的作用。我们已经确定肿瘤抑制因子Nischarin是LKB1的一个新的结合伙伴。我们的图谱分析表明，Nischarin的N端与LKB1的44-436个氨基酸相互作用。时间推移显微镜和Transwell迁移数据显示，从浸润性乳腺癌细胞系(MDA-MB-231)中缺失Nischarin和LKB1可以增强迁移，通过增加迁移细胞的距离和速度来衡量。我们的数据表明，这是PAK1和LIMK1磷酸化升高的结果。此外，Nischarin和LKB1的缺失增加了体内肿瘤的生长。与此相一致的是，流式细胞仪和增强的细胞周期蛋白D1显示，S期细胞的百分比增加。Nischarin和LKB1的缺失也导致肺转移形成的急剧增加。我们的研究首次证明了LKB1和Nischarin之间的功能相互作用可以抑制细胞迁移和乳腺肿瘤进展。从机制上，我们发现这两种蛋白共同调节PAK-LIMK-cofilin和细胞周期蛋白D1/CDK4通路。
Biallelic inactivation of LKB1, a serine/threonine kinase, has been detected in 30% of lung adenocarcinomas, and inhibition of breast tumor growth has been demonstrated. We have identified the tumor suppressor, Nischarin, as a novel binding partner of LKB1. Our mapping analysis shows that the N terminus of Nischarin interacts with amino acids 44-436 of LKB1. Time lapse microscopy and Transwell migration data show that the absence of both Nischarin and LKB1 from an invasive breast cancer cell line (MDA-MB-231) enhances migration as measured by increased distance and speed of migrating cells. Our data suggest that this is a result of elevated PAK1 and LIMK1 phosphorylation. Moreover, the absence of Nischarin and LKB1 increased tumor growth in vivo. Consistent with this, the percentage of S phase cells was increased, as demonstrated by flow cytometry and enhanced cyclin D1. The absence of Nischarin and LKB1 also led to a dramatic increase in the formation of lung metastases. Our studies, for the first time, demonstrate functional interaction between LKB1 and Nischarin to inhibit cell migration and breast tumor progression. Mechanistically, we show that these two proteins together regulate PAK-LIMK-Cofilin and cyclin D1/CDK4 pathways.