Research ArticleCancer

Phosphorylation of FADD by the kinase CK1α promotes KRASG12D-induced lung cancer

See allHide authors and affiliations

Sci. Signal.  27 Jan 2015:
Vol. 8, Issue 361, pp. ra9
DOI: 10.1126/scisignal.2005607

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

This article has a correction. Please see:

Conversion of a death adaptor to a proliferation mediator

Activating mutations in the protein RAS drive cell proliferation and tumor growth. Although best known for mediating cell death signaling through its death domain, when phosphorylated, the adaptor protein FADD promotes cell survival and proliferation. Bowman et al. found that, compared with KRAS mutant mice, KRAS mutant mice engineered to lack FADD or its upstream kinase CK1α developed fewer lung tumors. Lung tissue and cells from KRAS mutant mice had increased abundance of CK1α, phosphorylated FADD, and proliferative markers. In lung tumor samples from patients, expression of FADD was greater in tumors that had mutant KRAS. A CK1α inhibitor prevented FADD from physically interacting with mitotic kinases and suppressed cell proliferation in culture. Thus, blocking the phosphorylation of FADD may be a new strategy for patients with KRAS mutant lung tumors.

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 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.

View Full Text