title: HUWE1 ubiquitylates and degrades the RAC activator TIAM1 promoting cell-cell adhesion disassembly, migration, and invasion.
abstract: The E3 ubiquitin ligase HUWE1, deregulated in carcinoma, has been implicated in tumor formation. Here, we uncover a role for HUWE1 in cell migration and invasion through degrading the RAC activator TIAM1, implying an additional function in malignant progression. In MDCKII cells in response to HGF, HUWE1 catalyzes TIAM1 ubiquitylation and degradation predominantly at cell-cell adhesions, facilitating junction disassembly, migration, and invasion. Depleting HUWE1 or mutating the TIAM1 ubiquitylation site prevents TIAM1 degradation, antagonizing scattering, and invasion. Moreover, simultaneous depletion of TIAM1 restores migration and invasion in HUWE1-depleted cells. Significantly, we show that HUWE1 stimulates human lung cancer cell invasion through regulating TIAM1 stability. Finally, we demonstrate that HUWE1 and TIAM1 protein levels are inversely correlated in human lung carcinomas. Thus, we elucidate a critical role for HUWE1 in regulating epithelial cell-cell adhesion and provide additional evidence that ubiquitylation contributes to spatiotemporal control of RAC.
authors.affiliation: Cell Signalling Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.
authors.forename: Lynsey
authors.initials: L
authors.lastname: Vaughan
authors.affiliation: Cell Signalling Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.
authors.forename: Chong-Teik
authors.initials: CT
authors.lastname: Tan
authors.affiliation: Faculty of Life Sciences, The University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Chapman
authors.affiliation: Department of Histopathology, The Christie Hospital and Institute of Cancer Sciences, The University of Manchester, Manchester M20 4BX, UK.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nonaka
authors.affiliation: Cell Signalling Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Mack
authors.affiliation: Biological Mass Spectrometry, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.
authors.forename: Duncan
authors.initials: D
authors.lastname: Smith
authors.affiliation: Respiratory Research Group, Institute of Inflammation and Repair, The University of Manchester and North West Lung Centre, University Hospital of South Manchester, Manchester M23 9LT, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Booton
authors.affiliation: Faculty of Life Sciences, The University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Adam F L
authors.initials: AF
authors.lastname: Hurlstone
authors.affiliation: Cell Signalling Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK. Electronic address: angeliki.malliri@cruk.manchester.ac.uk.
authors.forename: Angeliki
authors.initials: A
authors.lastname: Malliri
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D002448:Cell Adhesion / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D004285:Dogs; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D061985:Madin Darby Canine Kidney Cells; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000473:pathology; D059748:Proteolysis; D015398:Signal Transduction / Q000235:genetics; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000235:genetics; D020744:rac GTP-Binding Proteins / Q000378:metabolism
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C087334:TIAM1 protein, human; D025521:Tumor Suppressor Proteins; C502830:HUWE1 protein, human; D044767:Ubiquitin-Protein Ligases; D020744:rac GTP-Binding Proteins