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Cited by 63Hippo pathway signaling and YAP/TAZCell Adhesion Molecules ResearchProtein Kinase Regulation and GTPase Signaling

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

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Wong, Kwong-Fai, Liu, Angela M., Hong, Wanjin, Xu, Zhi, Luk, John M.·2016·Oncotarget
DOI 10.18632/oncotarget.12760PMC PMC5363613
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Abstract

// Kwong-Fai Wong 1, 2 , Angela M. Liu 1, 2 , Wanjin Hong 3 , Zhi Xu 4 , John M. Luk 1, 2, 5, 6 1 Department of Pharmacology, National University Health System, Singapore 2 Department of Surgery, National University Health System, Singapore 3 Institute of Molecular and Cell Biology, Biopolis, Singapore 4 Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China 5 Department of Pathology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong 6 Department of Translational and Clinical Medicine, Arbele Limited, Hong Kong Science Park, Shatin, Hong Kong Correspondence to: John M. Luk, email: dr.johnluk@gmail.com Zhi Xu, email: michelle.xuzhi@hotmail.com Keywords: extracellular stimuli, hippo pathway, liver cancer, MST1, Yes-associated protein Received: August 01, 2016 Accepted: September 25, 2016 Published: October 19, 2016 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.

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  • β1 integrin signaling feeds back to the Hippo pathway, which can negatively regulate the expression of KIBRA.

    “β1 integrin signaling also feeds back to the Hippo pathway, which can negatively regulate the expression of KIBRA (Wong et al. 2016; Tokamov et al. 2021)”

    From The Serine/Threonine Kinase <scp>NDR2</scp> Regulates Integrin Signaling, Synapse Formation, and Synaptic Plasticity in the Hippocampus (2025) · cites this paper as Wong et al. 2016

    The Results section, “Extracellular matrix (ECM) adhesion by α2β1 integrin inhibits the Hippo pathway” (page unavailable), reports that collagen-bound α2β1 integrin inhibits Hippo pathway components in hepatocellular carcinoma cells. Our copy does not report that the Hippo pathway negatively regulates KIBRA expression; a search for KIBRA expression found no supporting passage. (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
Wong, K.-F., Liu, A. M., Hong, W., Xu, Z., & Luk, J. M.
Affiliations
  • National University Health System (SG)
  • Institute of Molecular and Cell Biology (SG)
  • Nanjing First Hospital (CN)
  • Queen Mary Hospital (CN)
ORCID
Venue
Oncotarget
Publisher
Impact Journals, LLC
Published
2016-10-19
Volume
7
Issue
47
Pages
77683-77695
ISSN
1949-2553 (ISSN-L)
DOI
10.18632/oncotarget.12760
PMC
PMC5363613
OpenAlex
W2535463508
Cited by
63
References
4
Citations by year
2026: 1 · 2025: 4 · 2024: 6 · 2023: 5 · 2022: 6 · 2021: 12 · 2020: 9 · 2019: 7 · 2018: 7 · 2017: 6
FWCI
4.59
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Oncotarget (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • National University of Singapore (submittedVersion, cc-by)
Funders
National Natural Science Foundation of China (81370057)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
  • Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
alpha2beta1 integrin, MST1, YAP, Hippo signaling pathway, hepatocellular carcinoma, collagen extracellular matrix, LATS1, connective tissue growth factor, cell adhesion, tumor progression, AXL receptor tyrosine kinase, gene expression signatures, ITGA2, oncogenic signaling, liver cancer
MeSH terms
YAP-Signaling Proteins, Cell Adhesion, Female, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Male, Phosphoproteins, Phosphorylation, Serine, Transcription Factors, Signal Transduction, Protein Serine-Threonine Kinases, Integrin beta1, Integrin alpha2, Cell Line, Tumor, Adaptor Proteins, Signal Transducing, Connective Tissue Growth Factor

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