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- Title
Phosphorylation of FADD by the kinase CK1α promotes KRAS<sup>G12D</sup>-induced lung cancer.
- Authors
Bowman, Brittany M.; Ross, Brian D.; Sebolt, Katrina A.; Beer, David G.; Rehemtulla, Alnawaz; Galbán, Stefanie; Hoff, Benjamin A.; Boes, Jennifer L.; Heist, Kevin A.; Galbán, Craig J.; Daniels, Danette L.; Patel, Rajiv M.; Zhang, Jianke
- 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 KRASG12D-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 1a). 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 theG2/M transition, including PLK1 (Polo-like kinase 1), AURKA (Aurora kinase A), and BUB1 (budding uninhibited by benzimidazoles 1). This interactionwas decreased in cells treated with a CKI-7, a CK1αinhibitor. Therefore, as the kinase that phosphorylates FADD downstream of RAS, CK1a may be a therapeutic target for KRAS-driven lung cancer.
- Subjects
PHOSPHORYLATION; MORT1 protein; CASEIN kinase; AURORA kinases; LUNG cancer
- Publication
Science Signaling, 2015, Vol 8, Issue 361, p1
- ISSN
1945-0877
- Publication type
Article
- DOI
10.1126/scisignal.2005607