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PAK4 kinase-mediated SCG10 phosphorylation involved in gastric cancer metastasis

Abstract

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.

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Acknowledgements

We thank Yongxi Song, Jianhua Wu and Feng Zhao for their technical assistance with the animal experiments. We are grateful to Gary M Bokoch, Audrey Minden and Bruce Mayer for providing essential expression vectors. This work was supported by grants from the National Natural Science Foundation of China (Nos 90813038, 31171360, 81230077 and 81130042) and Doctoral fund of Ministry of Education of China (No. 20102104110016).

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Guo, Q., Su, N., Zhang, J. et al. PAK4 kinase-mediated SCG10 phosphorylation involved in gastric cancer metastasis. Oncogene 33, 3277–3287 (2014). https://doi.org/10.1038/onc.2013.296

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