MEKK2 regulates paxillin ubiquitylation and localization in MDA-MB 231 breast cancer cells
MEKK2 regulates paxillin ubiquitylation and localization in MDA-MB 231 breast cancer cells
复制标题
DOI：
10.1042/bj20140420
复制
发表时间：
2014-11-15
影响因子：
4.1
通讯作者：
Cuevas, Bruce D.
中科院分区：
文献类型：
--
作者：
Ameka, Magdalene;Kahle, Michael P.;Cuevas, Bruce D.
细胞内激酶MEKK 2（促分裂原活化蛋白激酶/细胞外信号调节激酶2）是JNK（c-Jun N-末端激酶）的上游调节因子，但MEKK 2的其他功能尚未明确。在侵袭性乳腺肿瘤细胞中沉默MEKK 2表达显著抑制异种移植物转移，表明MEKK 2控制肿瘤进展所需的肿瘤细胞功能。在我们之前对MEKK 2功能的研究中，我们发现肿瘤细胞与纤连蛋白的附着将MEKK 2募集到粘着斑复合物，并且MEKK 2敲低与稳定的粘着斑和肿瘤细胞迁移的显著抑制相关。在本研究中，我们调查MEKK 2在粘着斑中的功能，我们报告MEKK 2与粘着斑蛋白桩蛋白的LD 1基序物理相关。我们发现，MEKK 2诱导桩蛋白泛素化，这种功能需要桩蛋白LD 1基序和MEKK 2激酶活性。最后，我们证明MEKK 2促进桩蛋白从局部粘连重新分布到细胞质中，但不促进桩蛋白降解。总之，我们的研究结果揭示了MEKK 2作为乳腺肿瘤细胞中泛素化依赖性桩蛋白再分布的调节剂的新功能。
The intracellular kinase MEKK2 (mitogen-activated protein kinase/extracellular-signal-regulated kinase kinase kinase 2) is an upstream regulator of JNK (c-Jun N-terminal kinase), but additional functions for MEKK2 have not been well defined. Silencing MEKK2 expression in invasive breast tumour cells markedly inhibits xenograft metastasis, indicating that MEKK2 controls tumour cell function required for tumour progression. In our previous investigation of MEKK2 function, we discovered that tumour cell attachment to fibronectin recruits MEKK2 to focal adhesion complexes, and that MEKK2 knockdown is associated with stabilized focal adhesions and significant inhibition of tumour cell migration. In the present study we investigate MEKK2 function in focal adhesions and we report that MEKK2 physically associates with the LD1 motif of the focal adhesion protein paxillin. We reveal that MEKK2 induces paxillin ubiquitylation, and that this function requires both the paxillin LD1 motif and MEKK2 kinase activity. Finally, we demonstrate that MEKK2 promotes paxillin redistribution from focal adhesions into the cytoplasm, but does not promote paxillin degradation. Taken together, our results reveal a novel function for MEKK2 as a regulator of ubiquitylation-dependent paxillin redistribution in breast tumour cells.