title: Inactivation of the Hippo tumour suppressor pathway by integrin-linked kinase.
abstract: One of the hallmarks of cancers is the silencing of tumour suppressor genes and pathways. The Hippo tumour suppressor pathway is inactivated in many types of cancers, leading to tumour progression and metastasis. However, the mechanisms of pathway inactivation in tumours remain unclear. Here we demonstrate that integrin-linked kinase (ILK) plays a critical role in the suppression of the Hippo pathway via phospho-inhibition of MYPT1-PP1, leading to inactivation of Merlin. Inhibition of ILK in breast, prostate and colon tumour cells results in the activation of the Hippo pathway components MST1 and LATS1 with concomitant inactivation of YAP/TAZ (Yes-associated protein/transcriptional co-activator with PDZ-binding motif) transcriptional co-activators and TEAD-mediated transcription. Genetic deletion of ILK suppresses ErbB2-driven YAP/TAZ activation in mammary tumours, and its pharmacological inhibition suppresses YAP activation and tumour growth in vivo. Our data demonstrate a role for ILK as a multiple receptor proximal regulator of Hippo tumour suppressor pathway and as a cancer therapeutic target.
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada V5Z 1L3.
authors.forename: Isabel
authors.initials: I
authors.lastname: Serrano
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada V5Z 1L3.
authors.forename: Paul C
authors.initials: PC
authors.lastname: McDonald
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada V5Z 1L3.
authors.forename: Frances
authors.initials: F
authors.lastname: Lock
authors.affiliation: Goodman Cancer Centre, McGill University, Montreal, Quebec, Canada H3A 1A3.
authors.forename: William J
authors.initials: WJ
authors.lastname: Muller
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada V5Z 1L3.
authors.forename: Shoukat
authors.initials: S
authors.lastname: Dedhar
mesh_terms: D000217:Acyltransferases; D000818:Animals; D017209:Apoptosis; D001932:Brain Neoplasms / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D005910:Glioma / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D000090683:Hippo Signaling Pathway; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D043263:Myosin-Light-Chain Phosphatase / Q000378:metabolism; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D025581:Neurofibromin 2 / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D000099200:Scaffold Protein ILK
chemical_list: D000217:Acyltransferases; D018797:Cell Cycle Proteins; D017228:Hepatocyte Growth Factor; D043263:Myosin-Light-Chain Phosphatase; D025581:Neurofibromin 2; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D014157:Transcription Factors; D000099200:Scaffold Protein ILK; C456659:YY1AP1 protein, human; C082332:macrophage stimulating protein; C108675:TAFAZZIN protein, human; C092745:LATS1 protein, human; C508053:ERBB2 protein, human; C490372:PPP1R12A protein, human