title: SHP2 positively regulates TGFβ1-induced epithelial-mesenchymal transition modulated by its novel interacting protein Hook1.
abstract: The epithelial-mesenchymal transition (EMT) is an essential process for embryogenesis. It also plays a critical role in the initiation of tumor metastasis. Src homology 2 (SH2)-domain containing protein-tyrosine phosphatase-2 (SHP2) is a ubiquitously expressed protein-tyrosine phosphatase and is mutated in many tumors. However, its functional role in tumor metastasis remains largely unknown. We found that TGFβ1-induced EMT in lung epithelial A549 cells was partially blocked when SHP2 was decreased by transfected siRNA. The constitutively active form (E76V) promoted EMT while the phosphatase-dead mutation (C459S) and the SHP2 inhibitor PHPS1 blocked EMT, which further demonstrated that the phosphatase activity of SHP2 was required for promoting TGFβ1-induced EMT. Using the protein-tyrosine phosphatase domain of SHP2 as bait, we identified a novel SHP2-interacting protein Hook1. Hook1 was down-regulated during EMT in A549 cells. Overexpression of Hook1 inhibited EMT while knockdown of Hook1 promoted EMT. Moreover, both the protein-tyrosine phosphatase domain and N-terminal SH2 domain of SHP2 directly interacted with Hook1. Down-regulation of Hook1 increased SHP2 activity. These results suggested that Hook1 was an endogenous negative regulator of SHP2 phosphatase activity. Our data showed that the protein-tyrosine phosphatase SHP2 was involved in the process of EMT and Hook1 repressed EMT by regulating the activation of SHP2. SHP2-Hook1 complex may play important roles in tumor metastases by regulating EMT in cancer cells.
authors.affiliation: From the Department of Pathology and Pathophysiology, Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Shuomin
authors.initials: S
authors.lastname: Li
authors.affiliation: The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China, and.
authors.forename: Linrun
authors.initials: L
authors.lastname: Wang
authors.affiliation: The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China, and.
authors.forename: Qingwei
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: From the Department of Pathology and Pathophysiology, Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China, and.
authors.forename: Lingjuan
authors.initials: L
authors.lastname: He
authors.affiliation: From the Department of Pathology and Pathophysiology, Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Qinqin
authors.initials: Q
authors.lastname: Xu
authors.affiliation: From the Department of Pathology and Pathophysiology, Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Sun
authors.affiliation: From the Department of Pathology and Pathophysiology, Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Li
authors.initials: L
authors.lastname: Teng
authors.affiliation: From the Department of Pathology and Pathophysiology, Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang 310003, China hqcheng11@zju.edu.cn.
authors.forename: Hongqiang
authors.initials: H
authors.lastname: Cheng
authors.affiliation: From the Department of Pathology and Pathophysiology, Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang 310003, China yke@zju.edu.cn.
authors.forename: Yuehai
authors.initials: Y
authors.lastname: Ke
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D011485:Protein Binding; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; C471055:hook1 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11
keywords: Epithelial to Mesenchymal Transition; Epithelial-Mesenchymal Transition (EMT); Hook1; Mesenchymal; Metastasis; Protein Phosphatase; Protein-Protein Interaction; Protein-tyrosine Phosphatase; shp2