Tyrosine phosphatase SHP2 increases cell motility in triple-negative breast cancer through the activation of SRC-family kinases
Tyrosine phosphatase SHP2 increases cell motility in triple-negative breast cancer through the activation of SRC-family kinases
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DOI：
10.1038/onc.2014.170
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发表时间：
2015-04-23
期刊：
影响因子：
8
通讯作者：
Bentires-Alj, M.
中科院分区：
文献类型：
--
作者：
Sausgruber, N.;Coissieux, M-M;Bentires-Alj, M.
肿瘤细胞迁移在转移的早期步骤中发挥着重要作用，转移是癌症的致命标志。在本研究中，我们研究了酪氨酸磷酸酶（含 SRC 同源 2 结构域的磷酸酶 2 (SHP2)）对转移性三阴性乳腺癌 (TNBC) 细胞迁移的影响，TNBC 是一种与预后不良相关的侵袭性疾病，目前尚无靶向治疗。使用小鼠模型和多光子活体成像，我们确定了 SHP2 对体内 TNBC 细胞运动的关键影响。此外，对 TNBC 细胞的分析表明，SHP2 还影响体外细胞迁移、趋化性和侵袭。无偏磷酸蛋白质组学和生化分析表明，SHP2 激活多种 SRC 家族激酶和下游靶标，其中大多数是迁移和侵袭的诱导剂。特别是，通过荧光共振能量转移测定揭示了 SHP2 和 c-SRC 之间的直接相互作用。这些结果表明，SHP2 是 TNBC 迁移到远处器官的早期步骤中的关键因素。
Tumor cell migration has a fundamental role in early steps of metastasis, the fatal hallmark of cancer. In the present study, we investigated the effects of the tyrosine phosphatase, SRC-homology 2 domain-containing phosphatase 2 (SHP2), on cell migration in metastatic triple-negative breast cancer (TNBC), an aggressive disease associated with a poor prognosis for which a targeted therapy is not yet available. Using mouse models and multiphoton intravital imaging, we have identified a crucial effect of SHP2 on TNBC cell motility in vivo. Further, analysis of TNBC cells revealed that SHP2 also influences cell migration, chemotaxis and invasion in vitro. Unbiased phosphoproteomics and biochemical analysis showed that SHP2 activates several SRC-family kinases and downstream targets, most of which are inducers of migration and invasion. In particular, direct interaction between SHP2 and c-SRC was revealed by a fluorescence resonance energy transfer assay. These results suggest that SHP2 is a crucial factor during early steps of TNBC migration to distant organs.