FGF21 Induced by the ASK1-p38 Pathway Promotes Mechanical Cell Competition by Attracting Cells.

Cell competition is a social cellular phenomenon in which unfit cells are selectively eliminated to maintain tissue homeostasis.1-3 Recent studies have revealed that mechanical forces induce competitive cell-cell interactions in Drosophila.4-6 This mechanical cell competition has also been reported to play an important role in mammalian cells, using Madin-Darby canine kidney (MDCK) cells depleted of a polarity regulator Scribble in a tetracycline-inducible manner (scribKD cells).7scribKD cells are hypersensitive to crowding due to the lower homeostatic density than wild-type (WT) cells,7,8 and in the context of cell competition, scribKD cells are compacted and eliminated by WT cells.7-10 Although p38 and p53 are involved in this process,7,10 the molecular mechanism by which WT cells recognize and mechanically eliminate scribKD cells remains unclear. Here, we report that scribKD cells secrete fibroblast growth factor 21 (FGF21) to drive cell competition. Knockdown of FGF21 in scribKD cells or loss of FGFR1 in WT cells suppresses cell competition, suggesting that WT cells recognize scribKD cells through FGF21. FGF21-containing culture medium of scribKD cells activates cell motility. Moreover, FGF21 promotes the compression and elimination of scribKD cells by attracting surrounding WT cells. We also demonstrate that activation of the apoptosis signal-regulating kinase 1 (ASK1)-p38 pathway in scribKD cells induces FGF21 to drive cell competition. Our findings reveal a mechanism whereby WT cells mechanically eliminate scribKD cells and propose a new function for FGF21 in cell-cell communication.

Apoptosis signal-regulating kinase 1 as a therapeutic target.

INTRODUCTION: All organisms are ordinarily exposed to various stresses. It is important for organisms to possess appropriate stress response mechanisms and to maintain homeostasis because the disruption of a stress response system can cause various diseases. Apoptosis signal-regulating kinase 1 (ASK1) is one of the stress-responsive MAP3Ks. ASK1 plays an important role in the response to reactive oxygen species (ROS), endoplasmic reticulum stress and pro-inflammatory cytokines, and it is involved in the pathogenesis of various diseases. AREAS COVERED: In this review, the authors describe recent literature concerning the intricate and elaborate regulation system of ASK1, the function of ASK1 during a cellular stress response and the involvement of ASK1 in many diseases, including cancer, neurodegenerative diseases, infections, diabetes and cardiovascular diseases. EXPERT OPINION: In certain disease conditions, ASK1 plays a protective role, whereas ASK1 can exacerbate the pathology of other diseases. Although ASK1 is involved in various diseases, there is no therapy or drug that targets ASK1 for use in a clinical setting. Recently, ASK1 inhibitors (K811 and MSC2032964A) have emerged, and their therapeutic potentials have been tested in vivo. ASK1 is currently receiving considerable attention as a new therapeutic target.

Roquin-2 promotes ubiquitin-mediated degradation of ASK1 to regulate stress responses.

Apoptosis signal-regulating kinase 1 (ASK1, also known as MAP3K5) mediates reactive oxygen species (ROS)-induced cell death. When activated by ROS, ASK1 ultimately becomes ubiquitinated and degraded by the proteasome, a process that is antagonized by the ubiquitin-specific protease USP9X. Using a functional siRNA (small interfering RNA) screen in HeLa cells, we identified Roquin-2 (also called RC3H2) as an E3 ubiquitin ligase required for ROS-induced ubiquitination and degradation of ASK1. In cells treated with H2O2, knockdown of Roquin-2 promoted sustained activation of ASK1 and the downstream stress-responsive kinases JNK (c-Jun amino-terminal kinase) and p38 MAPK (mitogen-activated protein kinase), and led to cell death. The nematode Caenorhabditis elegans produces ROS as a defense mechanism in response to bacterial infection. In C. elegans, mutation of the gene encoding the Roquin-2 ortholog RLE-1 promoted accumulation of the activated form of the ASK1 ortholog NSY-1 and conferred resistance to infection by the bacteria Pseudomonas aeruginosa. Thus, these data suggest that degradation of ASK1 mediated by Roquin-2 is an evolutionarily conserved mechanism required for the appropriate regulation of stress responses, including pathogen resistance and cell death.