title: LIM-domain protein AJUBA suppresses malignant mesothelioma cell proliferation via Hippo signaling cascade.
abstract: Malignant mesothelioma (MM) is one of the most aggressive neoplasms usually associated with asbestos exposure and is highly refractory to current therapeutic modalities. MMs show frequent activation of a transcriptional coactivator Yes-associated protein (YAP), which is attributed to the neurofibromatosis type 2 (NF2)-Hippo pathway dysfunction, leading to deregulated cell proliferation and acquisition of a malignant phenotype. However, the whole mechanism of disordered YAP activation in MMs has not yet been well clarified. In the present study, we investigated various components of the NF2-Hippo pathway, and eventually found that MM cells frequently showed downregulation of LIM-domain protein AJUBA, a binding partner of large tumor suppressor type 2 (LATS2), which is one of the last-step kinases of the NF2-Hippo pathway. Although loss of AJUBA expression was independent of the alteration status of other Hippo pathway components, MM cell lines with AJUBA inactivation showed a more dephosphorylated (activated) level of YAP. Immunohistochemical analysis showed frequent downregulation of AJUBA in primary MMs, which was associated with YAP constitutive activation. We found that AJUBA transduction into MM cells significantly suppressed promoter activities of YAP-target genes, and the suppression of YAP activity by AJUBA was remarkably canceled by knockdown of LATS2. In connection with these results, transduction of AJUBA-expressing lentivirus significantly inhibited the proliferation and anchorage-independent growth of the MM cells that harbored ordinary LATS family expression. Taken together, our findings indicate that AJUBA negatively regulates YAP activity through the LATS family, and inactivation of AJUBA is a novel key mechanism in MM cell proliferation.
authors: 1] Department of Thoracic Oncology Oncology, Aichi Cancer Center Research Institute, Nagoya, Japan [2] Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: I
authors: I
authors: Tanaka
authors: 1] Department of Thoracic Oncology Oncology, Aichi Cancer Center Research Institute, Nagoya, Japan [2] Department of Cancer Genetics, Program in Function Construction Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: H
authors: H
authors: Osada
authors: Department of Thoracic Oncology Oncology, Aichi Cancer Center Research Institute, Nagoya, Japan.
authors: M
authors: M
authors: Fujii
authors: 1] Department of Thoracic Oncology Oncology, Aichi Cancer Center Research Institute, Nagoya, Japan [2] Department of Cancer Genetics, Program in Function Construction Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: A
authors: A
authors: Fukatsu
authors: Department of Thoracic Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.
authors: T
authors: T
authors: Hida
authors: Department of Thoracic Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.
authors: Y
authors: Y
authors: Horio
authors: Department of Thoracic Oncology Oncology, Aichi Cancer Center Research Institute, Nagoya, Japan.
authors: Y
authors: Y
authors: Kondo
authors: Department of Pathology, Hyogo College of Medicine, Nishinomiya, Japan.
authors: A
authors: A
authors: Sato
authors: Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Y
authors: Y
authors: Hasegawa
authors: Department of Pathology, Hyogo College of Medicine, Nishinomiya, Japan.
authors: T
authors: T
authors: Tsujimura
authors: 1] Department of Thoracic Oncology Oncology, Aichi Cancer Center Research Institute, Nagoya, Japan [2] Department of Cancer Genetics, Program in Function Construction Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Y
authors: Y
authors: Sekido
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003593:Cytoplasm / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D000090683:Hippo Signaling Pathway; D006801:Humans; D007150:Immunohistochemistry; D060588:LIM Domain Proteins / Q000378:metabolism*; D016086:Lentivirus / Q000235:genetics; D008175:Lung Neoplasms / Q000378:metabolism*; D008654:Mesothelioma / Q000378:metabolism*; D000086002:Mesothelioma, Malignant; D025581:Neurofibromin 2 / Q000378:metabolism; D010641:Phenotype; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins
chemical_list: C485608:AJUBA protein, human; D048868:Adaptor Proteins, Signal Transducing; D060588:LIM Domain Proteins; D025581:Neurofibromin 2; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D017346:Protein Serine-Threonine Kinases