title: MST3 promotes proliferation and tumorigenicity through the VAV2/Rac1 signal axis in breast cancer.
abstract: 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 (âP-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 âP-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.
authors.affiliation: Department of Biochemistry and Molecular Biology, National Cheng Kung University, Tainan, Taiwan, ROC.|Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan, ROC.|Center for Infectious Diseases and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.
authors.forename: Chien-Yu
authors.initials: CY
authors.lastname: Cho
authors.affiliation: Department of Surgery, National Cheng Kung University, Tainan, Taiwan, ROC.
authors.forename: Kuo-Ting
authors.initials: KT
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Biology, National Cheng Kung University, Tainan, Taiwan, ROC.|Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan, ROC.
authors.forename: Wei-Ching
authors.initials: WC
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, National Cheng Kung University, Tainan, Taiwan, ROC.|Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan, ROC.
authors.forename: Chih-Yang
authors.initials: CY
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, National Cheng Kung University, Tainan, Taiwan, ROC.|Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan, ROC.
authors.forename: Yung-Sheng
authors.initials: YS
authors.lastname: Chang
authors.affiliation: Department of Biochemistry and Molecular Biology, National Cheng Kung University, Tainan, Taiwan, ROC.|Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan, ROC.
authors.forename: Hau-Lun
authors.initials: HL
authors.lastname: Huang
authors.affiliation: Department of Surgery, National Cheng Kung University, Tainan, Taiwan, ROC.
authors.forename: Hui-Ping
authors.initials: HP
authors.lastname: Hsu
authors.affiliation: Department of Emergency Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC.
authors.forename: Meng-Chi
authors.initials: MC
authors.lastname: Yen
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan, ROC.|Graduate Institute of Immunology, National Taiwan University, Taipei, Taiwan, ROC.
authors.forename: Ming-Zong
authors.initials: MZ
authors.lastname: Lai
authors.affiliation: Department of Biochemistry and Molecular Biology, National Cheng Kung University, Tainan, Taiwan, ROC.|Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan, ROC.|Center for Infectious Diseases and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.
authors.forename: Ming-Derg
authors.initials: MD
authors.lastname: Lai
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009367:Neoplasm Staging; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D000099317:Hippo Kinases
chemical_list: D014408:Biomarkers, Tumor; D017346:Protein Serine-Threonine Kinases; D051567:Proto-Oncogene Proteins c-vav; D020830:rac1 GTP-Binding Protein; C107953:RAC1 protein, human; C093651:VAV2 protein, human; C109163:STK24 protein, human; D000099317:Hippo Kinases
keywords: MST3; Rac1; VAV2; breast cancer; cyclin D1