Research Papers:

MST3 promotes proliferation and tumorigenicity through the VAV2/Rac1 signal axis in breast cancer

Chien-Yu Cho, Kuo-Ting Lee, Wei-Ching Chen, Chih-Yang Wang, Yung-Sheng Chang, Hau-Lun Huang, Hui-Ping Hsu, Meng-Chi Yen, Ming-Zong Lai and Ming-Derg Lai _

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Oncotarget. 2016; 7:14586-14604. https://doi.org/10.18632/oncotarget.7542

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Chien-Yu Cho1,2,4, Kuo-Ting Lee3, Wei-Ching Chen1,2, Chih-Yang Wang1,2, Yung-Sheng Chang1,2, Hau-Lun Huang1,2, Hui-Ping Hsu3, Meng-Chi Yen5, Ming-Zong Lai6,7 and Ming-Derg Lai1,2,4

1 Department of Biochemistry and Molecular Biology, National Cheng Kung University, Tainan, Taiwan, ROC

2 Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan, ROC

3 Department of Surgery, National Cheng Kung University, Tainan, Taiwan, ROC

4 Center for Infectious Diseases and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC

5 Department of Emergency Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC

6 Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan, ROC

7 Graduate Institute of Immunology, National Taiwan University, Taipei, Taiwan, ROC

Correspondence to:

Ming-Derg Lai, email:

Keywords: MST3, VAV2, Rac1, cyclin D1, breast cancer

Received: July 07, 2015 Accepted: January 02, 2016 Published: February 20, 2016


MST3 (mammalian STE20-like kinase 3) belongs to the Ste20 serine/threonine protein kinase family. The role of MST3 in tumor growth is less studied; therefore, we investigates the function of MST3 in breast cancer. Here, we demonstrate that MST3 is overexpressed in human breast tumors. Online Kaplan-Meier plotter analysis reveals that overexpression of MST3 predicts poor prognosis in breast cancer patients. Knockdown of MST3 with shRNA inhibits proliferation and anchorage-independent growth in vitro. Downregulation of MST3 in triple-negative MDA-MB-231 and MDA-MB-468 breast cancer cells decreases tumor formation in NOD/SCID mice. MST3 interacts with VAV2, but not VAV3, as demonstrated by co-immunoprecipitation and confocal microscopy. By domain mapping of MST3, we determine that the proline-rich region of MST3 (353KDIPKRP359) interacts with the SH3 domain of VAV2. Mutation of the two proline residues in this domain significantly attenuates the interaction between MST3 and VAV2. Overexpression of wild-type MST3 (WT-MST3), but not proline-rich-deleted MST3 (∆P-MST3), enhances the proliferation rate and anchorage-independent growth of MDA-MB-468 cells. Overexpression of MST3 increases VAV2 phosphorylation and GTP-Rac1, whereas downregulation of MST3 or delivery of ∆P-MST3 results in a reduction of VAV2 and Rac1 activation. Knockdown of MST3 inhibits cyclin D1 protein expression. The Rac1 inhibitor EHop-016 attenuates cell proliferation induced by WT-MST3. Finally, Knockdown of MST3 or Rac1 inhibitor decreases cyclin D protein expression, which is important for tumor growth. These results indicate that MST3 interacts with VAV2 to activate Rac1 and promote the tumorigenicity of breast cancer.

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