title: Integrin α2β1 inhibits MST1 kinase phosphorylation and activates Yes-associated protein oncogenic signaling in hepatocellular carcinoma.
abstract: The Hippo pathway regulates the down-stream target Yes-associated protein (YAP) to maintain organ homeostasis, which is commonly inactivated in many types of cancers. However, how cell adhesion dysregulates the Hippo pathway activating YAP oncogene in hepatocellular carcinoma (HCC) remains unclear. Our findings demonstrate that α2β1 integrin (but not other β1 integrins) expressed in HCC cells, after binding to collagen extracellular matrix, could inhibit MST1 kinase phosphorylation and activate YAP pro-oncogenic activities. Knockdown of integrin α2 gene (ITGA2) suppressed YAP targeted gene expression in vitro. α2β1 and collagen binding resulted in suppressing Hippo signaling of mammalian sterile 20-like kinase 1 (MST1) and Large tumor suppressor homolog 1 (LATS1) with concomitant activation of YAP-mediated connective tissue growth factor (CTGF) gene expression. In vitro kinase assay showed that MST1 is an immediate downstream target of integrin α2 with S1180 residue as the critical phosphorylation site. Clinical correlational analysis using a gene expression dataset of 228 HCC tumors revealed that ITGA2 expression was significantly associated with tumor progression, and co-expression with YAP targeted genes (AXL receptor tyrosine kinase, CTGF, cyclin D1, glypican 3, insulin like growth factor 1 receptor, and SRY-box 4) correlated with survivals of HCC patients. In conclusion, α2β1 integrin activation through cellular adhesion impacts the Hippo pathway in solid tumors and modulates MST1-YAP signaling cascade. Targeting integrin α2 holds promises for treating YAP-positive HCC.
authors.affiliation: Department of Pharmacology, National University Health System, Singapore.|Department of Surgery, National University Health System, Singapore.
authors.forename: Kwong-Fai
authors.initials: KF
authors.lastname: Wong
authors.affiliation: Department of Pharmacology, National University Health System, Singapore.|Department of Surgery, National University Health System, Singapore.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Liu
authors.affiliation: Institute of Molecular and Cell Biology, Biopolis, Singapore.
authors.forename: Wanjin
authors.initials: W
authors.lastname: Hong
authors.affiliation: Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, National University Health System, Singapore.|Department of Surgery, National University Health System, Singapore.|Department of Pathology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.|Department of Translational and Clinical Medicine, Arbele Limited, Hong Kong Science Park, Shatin, Hong Kong.
authors.forename: John M
authors.initials: JM
authors.lastname: Luk
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D055513:Connective Tissue Growth Factor; D005260:Female; D006801:Humans; D039421:Integrin alpha2 / Q000235:genetics*; D019012:Integrin beta1 / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C526317:CCN2 protein, human; D039421:Integrin alpha2; D019012:Integrin beta1; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D055513:Connective Tissue Growth Factor; D012694:Serine; C092745:LATS1 protein, human; C000614519:mammalian sterile 20-like kinase 1, human; D017346:Protein Serine-Threonine Kinases
keywords: MST1; Yes-associated protein; extracellular stimuli; hippo pathway; liver cancer