title: Llgl1 prevents metaplastic survival driven by epidermal growth factor dependent migration.
abstract: We have previously demonstrated that Llgl1 loss results in a gain of mesenchymal phenotypes and a loss of apicobasal and planar polarity. We now demonstrate that these changes represent a fundamental shift in cellular phenotype. Llgl1 regulates the expression of multiple cell identity markers, including CD44, CD49f, and CD24, and the nuclear translocation of TAZ and Slug. Cells lacking Llgl1 form mammospheres, where survival and transplantability is dependent upon the Epidermal Growth Factor Receptor (EGFR). Additionally, Llgl1 loss allows cells to grow in soft-agar and maintain prolonged survival as orthotopic transplants in NOD-SCIDmice. Lineage tracing and wound healing experiments demonstrate that mammosphere survival is due to enhanced EGF-dependent migration. The loss of Llgl1 drives EGFR mislocalization and an EGFR mislocalization point mutation (P667A) drives these same phenotypes, including activation of AKT and TAZ nuclear translocation. Together, these data indicate that the loss of Llgl1 results in EGFR mislocalization, promoting pre-neoplastic changes.
authors.affiliation: Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona.
authors.forename: Erin
authors.initials: E
authors.lastname: Greenwood
authors.affiliation: Arizona Cancer Center, University of Arizona, Tucson, Arizona.|Cancer Biology Program, University of Arizona, Tucson, Arizona.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Maisel
authors.affiliation: Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona.
authors.forename: David
authors.initials: D
authors.lastname: Ebertz
authors.affiliation: Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona.|Genetics Program, University of Arizona, Tucson, Arizona.
authors.forename: Atlantis
authors.initials: A
authors.lastname: Russ
authors.affiliation: Arizona Cancer Center, University of Arizona, Tucson, Arizona.|Department of Cell and Molecular Medicine, University of Arizona, Tucson, Arizona.
authors.forename: Ritu
authors.initials: R
authors.lastname: Pandey
authors.affiliation: Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona.|Arizona Cancer Center, University of Arizona, Tucson, Arizona.|BIO5 Institute, University of Arizona, Tucson, Arizona.|Genetics Program, University of Arizona, Tucson, Arizona.|Cancer Biology Program, University of Arizona, Tucson, Arizona.
authors.forename: Joyce
authors.initials: J
authors.lastname: Schroeder
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D051927:CD24 Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D019070:Cell Lineage; D002465:Cell Movement; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D039503:Integrin alpha6 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010641:Phenotype; D015398:Signal Transduction; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D014945:Wound Healing
chemical_list: D051927:CD24 Antigen; C497889:CD24 protein, human; C497483:CD44 protein, human; D003598:Cytoskeletal Proteins; D018960:Hyaluronan Receptors; D039503:Integrin alpha6; D047908:Intracellular Signaling Peptides and Proteins; C097906:LLGL1 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; C551991:WWTR1 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: Llgl1; TAZ; epidermal growth factor receptor; migration; polarity