title: Glutaminase 2 is a novel negative regulator of small GTPase Rac1 and mediates p53 function in suppressing metastasis.
abstract: Glutaminase (GLS) isoenzymes GLS1 and GLS2 are key enzymes for glutamine metabolism. Interestingly, GLS1 and GLS2 display contrasting functions in tumorigenesis with elusive mechanism; GLS1 promotes tumorigenesis, whereas GLS2 exhibits a tumor-suppressive function. In this study, we found that GLS2 but not GLS1 binds to small GTPase Rac1 and inhibits its interaction with Rac1 activators guanine-nucleotide exchange factors, which in turn inhibits Rac1 to suppress cancer metastasis. This function of GLS2 is independent of GLS2 glutaminase activity. Furthermore, decreased GLS2 expression is associated with enhanced metastasis in human cancer. As a p53 target, GLS2 mediates p53's function in metastasis suppression through inhibiting Rac1. In summary, our results reveal that GLS2 is a novel negative regulator of Rac1, and uncover a novel function and mechanism whereby GLS2 suppresses metastasis. Our results also elucidate a novel mechanism that contributes to the contrasting functions of GLS1 and GLS2 in tumorigenesis.
authors.affiliation: Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, United States.
authors.forename: Cen
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, United States.
authors.forename: Juan
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, United States.
authors.forename: Yuhan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, United States.
authors.forename: Xuetian
authors.initials: X
authors.lastname: Yue
authors.affiliation: Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, United States.|Department of Neurosurgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, United States.
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, United States.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, United States.
authors.forename: Felix
authors.initials: F
authors.lastname: Blanco
authors.affiliation: Department of Surgery, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, United States.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Molecular Biology, Biochemistry & Physics, Rutgers, The State University of New Jersey, Piscataway, United States.
authors.forename: Gyan
authors.initials: G
authors.lastname: Bhanot
authors.affiliation: Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, United States.
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Haffty
authors.affiliation: Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, United States.
authors.forename: Wenwei
authors.initials: W
authors.lastname: Hu
authors.affiliation: Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, United States.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Feng
mesh_terms: D045744:Cell Line, Tumor; D005972:Glutaminase / Q000378:metabolism*; D006801:Humans; D009362:Neoplasm Metastasis; D011485:Protein Binding; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; C586504:GLS2 protein, human; D005972:Glutaminase; D020830:rac1 GTP-Binding Protein
keywords: GLS2; Rac1; chromosomes; genes; human; metastasis; mouse; p53; tumor suppression