Research Papers:

Integrin α2β1 inhibits MST1 kinase phosphorylation and activates Yes-associated protein oncogenic signaling in hepatocellular carcinoma

Kwong-Fai Wong, Angela M. Liu, Wanjin Hong, Zhi Xu and John M. Luk _

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Oncotarget. 2016; 7:77683-77695. https://doi.org/10.18632/oncotarget.12760

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Kwong-Fai Wong1,2, Angela M. Liu1,2, Wanjin Hong3, Zhi Xu4, John M. Luk1,2,5,6

1Department of Pharmacology, National University Health System, Singapore

2Department of Surgery, National University Health System, Singapore

3Institute of Molecular and Cell Biology, Biopolis, Singapore

4Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China

5Department of Pathology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong

6Department of Translational and Clinical Medicine, Arbele Limited, Hong Kong Science Park, Shatin, Hong Kong

Correspondence to:

John M. Luk, email: [email protected]

Zhi Xu, email: [email protected]

Keywords: extracellular stimuli, hippo pathway, liver cancer, MST1, Yes-associated protein

Received: August 01, 2016    Accepted: September 25, 2016    Published: October 19, 2016


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.

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