MLK3 Regulates Paxillin Phosphorylation in Chemokine-Mediated Breast Cancer Cell Migration and Invasion to Drive Metastasis
MLK3 Regulates Paxillin Phosphorylation in Chemokine-Mediated Breast Cancer Cell Migration and Invasion to Drive Metastasis
复制标题
DOI：
10.1158/0008-5472.can-12-0655
复制
发表时间：
2012-08-15
期刊：
影响因子：
11.2
通讯作者：
Gallo, Kathleen A.
中科院分区：
文献类型：
--
作者：
Chen, Jian;Gallo, Kathleen A.
MLK3激酶激活多种有丝分裂原活化蛋白激酶，在癌细胞迁移和侵袭中起关键作用。在肿瘤微环境中，前转移因子驱动乳腺癌侵袭转移，但其相关信号通路尚不清楚。在这里，我们提供证据表明MLK3是趋化因子（CXCL12）诱导的基底乳腺癌细胞侵袭所必需的。我们发现MLK3诱导局灶黏着支架paxillin在Ser 178和Tyr 118上的强烈磷酸化，该磷酸化被MLK3- jnk的沉默或抑制所阻断。MLK3的沉默或抑制、JNK的抑制或paxillin S178A的表达均导致Rho活性增强，表明MLK3-JNK-paxillin轴限制了Rho活性，促进了局灶黏着的转换和迁移。与此一致的是，MLK3沉默增加了乳腺癌细胞的局灶粘连和应力纤维。MLK3沉默也减少了体内乳腺癌肺转移的形成，小鼠肺转移源的乳腺癌细胞显示Ser 178 paxillin磷酸化增强。综上所述，我们的研究结果表明MLK3-JNK-paxillin信号轴可能代表乳腺癌转移的潜在治疗靶点和/或预后标志物。癌症Res;72 (16);4130 - 40。(c) 2012年aacr。
MLK3 kinase activates multiple mitogen-activated protein kinases and plays a critical role in cancer cell migration and invasion. In the tumor microenvironment, prometastatic factors drive breast cancer invasion and metastasis, but their associated signaling pathways are not well-known. Here, we provide evidence that MLK3 is required for chemokine (CXCL12)-induced invasion of basal breast cancer cells. We found that MLK3 induced robust phosphorylation of the focal adhesion scaffold paxillin on Ser 178 and Tyr 118, which was blocked by silencing or inhibition of MLK3-JNK. Silencing or inhibition of MLK3, inhibition of JNK, or expression of paxillin S178A all led to enhanced Rho activity, indicating that the MLK3-JNK-paxillin axis limits Rho activity to promote focal adhesion turnover and migration. Consistent with this, MLK3 silencing increased focal adhesions and stress fibers in breast cancer cells. MLK3 silencing also decreased the formation of breast cancer lung metastases in vivo, and breast cancer cells derived from mouse lung metastases showed enhanced Ser 178 paxillin phosphorylation. Taken together, our findings suggest that the MLK3-JNK-paxillin signaling axis may represent a potential therapeutic target and/or prognostic marker in breast cancer metastasis. Cancer Res; 72(16); 4130-40. (C) 2012 AACR.