PAK4 kinase-mediated SCG10 phosphorylation involved in gastric cancer metastasis
PAK4 kinase-mediated SCG10 phosphorylation involved in gastric cancer metastasis
复制标题
PAK4激酶介导的SCG10磷酸化参与胃癌转移
DOI：
10.1038/onc.2013.296
复制
发表时间：
2014-06-19
期刊：
影响因子：
8
通讯作者：
Li, F.
中科院分区：
文献类型：
--
作者：
Guo, Q.;Su, N.;Li, F.
上级颈神经节10（SCG 10），作为微管（MT）的不稳定剂，维持MT稳态，并在神经元发育中具有关键作用，但其在肿瘤发生中的功能尚未被表征。在本研究中，我们证明了p21激活激酶4（PAK 4）介导的SCG 10磷酸化调节转移性胃癌中MT的稳态。我们的研究结果表明，SCG 10是PAK 4的生理底物，其以PAK 4依赖的方式在丝氨酸50（Ser 50）上磷酸化。磷酸化SCG 10调节MT动力学促进胃癌细胞体外迁移和侵袭以及异种移植小鼠模型中的转移。通过LCH-7749944或RNA干扰抑制PAK 4导致Ser 50磷酸化的抑制和对细胞侵袭的阻断，表明PAK 4-SCG 10信号传导在胃癌细胞侵袭中发生。此外，我们证明了PAK 4和磷酸化Ser 50 SCG 10在胃癌样品中的表达之间的强正相关性。我们还发现SCG 10磷酸化丝氨酸50的高表达与临床胃癌的侵袭性表型高度相关。这些发现揭示了SCG 10在促进胃癌细胞侵袭能力方面的新功能，表明阻断PAK 4介导的SCG 10磷酸化可能是胃癌转移的潜在治疗策略。
Superior cervical ganglia 10 (SCG10), as a microtubule (MT) destabilizer, maintains MT homeostasis and has a critical role in neuronal development, but its function in tumorigenesis has not been characterized. In the present study, we demonstrated that p21-activated kinase 4 (PAK4)-mediated SCG10 phosphorylation regulates MT homeostasis in metastatic gastric cancer. Our results indicate that SCG10 is a physiological substrate of PAK4, which is phosphorylated on serine 50 (Ser50) in a PAK4-dependent manner. Phosphorylated SCG10 regulated MT dynamics to promote gastric cancer cell migration and invasion in vitro and metastasis in a xenograft mouse models. Inhibiting PAK4, either by LCH-7749944 or RNA interference, resulted in the inhibition of Ser50 phosphorylation and a blockade to cell invasion, suggesting that PAK4-SCG10 signaling occurs in gastric cancer cell invasion. Moreover, we demonstrated a strong positive correlation between PAK4 and phospho-Ser50 SCG10 expression in gastric cancer samples. We also showed that high expression of SCG10 phospho-Ser50 is highly correlated to an aggressive phenotype of clinical gastric cancer. These findings revealed a novel function of SCG10 in promoting invasive potential of gastric cancer cells, suggesting that blocking PAK4-mediated SCG10 phosphorylation might be a potential therapeutic strategy for metastasis of gastric cancer.