title: Hyperactivation of EGFR and downstream effector phospholipase D1 by oncogenic FAM83B.
abstract: Despite the progress made in targeted anticancer therapies in recent years, challenges remain. The identification of new potential targets will ensure that the arsenal of cancer therapies continues to expand. FAM83B was recently discovered in a forward genetic screen for novel oncogenes that drive human mammary epithelial cell (HMEC) transformation. We report here that elevated FAM83B expression increases Phospholipase D (PLD) activity, and that suppression of PLD1 activity prevents FAM83B-mediated transformation. The increased PLD activity is engaged by hyperactivation of epidermal growth factor receptor (EGFR), which is regulated by an interaction involving FAM83B and EGFR. Preventing the FAM83B/EGFR interaction by site-directed mutation of lysine 230 of FAM83B suppressed PLD activity and MAPK signaling. Furthermore, ablation of FAM83B expression from breast cancer cells inhibited EGFR phosphorylation and suppressed cell proliferation. We propose that understanding the mechanism of FAM83B-mediated transformation will provide a foundation for future therapies aimed at targeting its function as an intermediary in EGFR, MAPK and mTOR activation.
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: R
authors.initials: R
authors.lastname: Cipriano
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: B L
authors.initials: BL
authors.lastname: Bryson
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: K L S
authors.initials: KL
authors.lastname: Miskimen
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Bartel
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: W
authors.initials: W
authors.lastname: Hernandez-Sanchez
authors.affiliation: Department of Pharmacology, The Vanderbilt Institute of Chemical Biology, The Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: R C
authors.initials: RC
authors.lastname: Bruntz
authors.affiliation: Department of Pharmacology, The Vanderbilt Institute of Chemical Biology, The Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Scott
authors.affiliation: Departments of Pharmacology and Chemistry, The Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: C W
authors.initials: CW
authors.lastname: Lindsley
authors.affiliation: Departments of Pharmacology, Chemistry, and Biochemistry, The Vanderbilt Institute of Chemical Biology, The Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: H A
authors.initials: HA
authors.lastname: Brown
authors.affiliation: 1] Department of Pathology, Case Western Reserve University, Cleveland, OH, USA [2] Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: M W
authors.initials: MW
authors.lastname: Jackson
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D048708:Cell Growth Processes / Q000502:physiology; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009857:Oncogenes / Q000235:genetics*; D010739:Phospholipase D / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction
chemical_list: C530220:FAM83A protein, human; D009363:Neoplasm Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D010739:Phospholipase D; C106801:phospholipase D1
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