title: Phosphorylation of FADD by the kinase CK1α promotes KRASG12D-induced lung cancer.
abstract: Genomic amplification of the gene encoding and phosphorylation of the protein FADD (Fas-associated death domain) is associated with poor clinical outcome in lung cancer and in head and neck cancer. Activating mutations in the guanosine triphosphatase RAS promotes cell proliferation in various cancers. Increased abundance of phosphorylated FADD in patient-derived tumor samples predicts poor clinical outcome. Using immunohistochemistry analysis and in vivo imaging of conditional mouse models of KRAS(G12D)-driven lung cancer, we found that the deletion of the gene encoding FADD suppressed tumor growth, reduced the proliferative index of cells, and decreased the activation of downstream effectors of the RAS-MAPK (mitogen-activated protein kinase) pathway that promote the cell cycle, including retinoblastoma (RB) and cyclin D1. In mouse embryonic fibroblasts, the induction of mitosis upon activation of KRAS required FADD and the phosphorylation of FADD by CK1α (casein kinase 1α). Deleting the gene encoding CK1α in KRAS mutant mice abrogated the phosphorylation of FADD and suppressed lung cancer development. Phosphorylated FADD was most abundant during the G2/M phase of the cell cycle, and mass spectrometry revealed that phosphorylated FADD interacted with kinases that mediate the G2/M transition, including PLK1 (Polo-like kinase 1), AURKA (Aurora kinase A), and BUB1 (budding uninhibited by benzimidazoles 1). This interaction was decreased in cells treated with a CKI-7, a CK1α inhibitor. Therefore, as the kinase that phosphorylates FADD downstream of RAS, CK1α may be a therapeutic target for KRAS-driven lung cancer.
authors: Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Brittany M
authors: BM
authors: Bowman
authors: Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Katrina A
authors: KA
authors: Sebolt
authors: Department of Radiology, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Benjamin A
authors: BA
authors: Hoff
authors: Department of Radiology, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Jennifer L
authors: JL
authors: Boes
authors: Promega Corporation, Madison, WI 53711, USA.
authors: Danette L
authors: DL
authors: Daniels
authors: Department of Radiology, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Kevin A
authors: KA
authors: Heist
authors: Department of Radiology, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Craig J
authors: CJ
authors: Galbán
authors: Departments of Pathology and Dermatology, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Rajiv M
authors: RM
authors: Patel
authors: Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors: Jianke
authors: J
authors: Zhang
authors: Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA.
authors: David G
authors: DG
authors: Beer
authors: Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA. Department of Radiology, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Brian D
authors: BD
authors: Ross
authors: Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA. alnawaz@umich.edu.
authors: Alnawaz
authors: A
authors: Rehemtulla
authors: Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Stefanie
authors: S
authors: Galbán
mesh_terms: D000818:Animals; D064096:Aurora Kinase A / Q000378:metabolism; D015153:Blotting, Western; D048128:Casein Kinase Ialpha / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism*; D005838:Genotype; D006652:Histological Techniques; D047468:Immunoprecipitation; D008163:Luminescent Measurements; D008175:Lung Neoplasms / Q000235:genetics*; D013058:Mass Spectrometry; D051379:Mice; D020125:Mutation, Missense / Q000235:genetics*; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D055114:X-Ray Microtomography; D000097869:Polo-Like Kinase 1
chemical_list: D064096:Aurora Kinase A; D048128:Casein Kinase Ialpha; D018797:Cell Cycle Proteins; D017931:DNA Primers; D053200:Fas-Associated Death Domain Protein; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D000097869:Polo-Like Kinase 1; C505534:Fadd protein, mouse; C576918:Aurka protein, mouse; C584281:Bub1 protein, mouse; C495971:Hras protein, mouse
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