The actin cross-linker Filamin/Cheerio mediates tumor malignancy downstream of JNK signaling

Abstract

SummaryCell shape dynamics, motility, and cell proliferation all depend on the actin cytoskeleton. Malignant cancer cells hijack the actin network to grow and migrate to secondary sites. Understanding the function of actin regulators is therefore of major interest. In the present study, we identify the actin cross-linking protein Filamin/Cheerio (Cher) as a mediator of malignancy in genetically defined Drosophila tumors. We show that in invasive tumors, resulting from cooperation of activated Ras with disrupted epithelial cell polarity, Cher is upregulated in a Jun N-terminal kinase (JNK)-dependent manner. Although dispensable in normal epithelium, Cher becomes required in the tumor cells for their growth and invasiveness. When deprived of Cher, these tumor clones lose their full potential to proliferate and breach tissue boundaries. Instead, the Cher-deficient clones remain confined within the limits of their source epithelium, permitting survival of the host animal. Through interaction with the myosin II heavy chain subunit, Cher is likely to strengthen the cortical actomyosin network and reinforce mechanical tension within the invasive tumors. Accordingly, Cher is required for aberrant expression of genes downstream of the Hippo/Yorkie signaling in the tumor tissue. Our study identifies Cher as a new target of JNK signaling that links cytoskeleton dynamics to tumor progression.

Slit-Robo Repulsive Signaling Extrudes Tumorigenic Cells from Epithelia

“…Notably, Slit’s highly conserved human homolog (Slit2) and human Robo2 both possess human AP1 binding sites (ATGAGTCAT; three in Slit2 and nine in Robo2, data not shown), supporting that JNK-activated Slit-Robo could occur in mammals. Interestingly, in scrib + Ras V1 2 tumors, JNK upregulates the actin crosslinker Filamin/Cheerio to mediate metastasis (Külshammer and Uhlirova, 2013). Different JNK-activated actin regulators may therefore prevent or promote tumorigenesis depending on the tumor’s genetic context.…”

F-actin binding protein, anillin, regulates integrity of intercellular junctions in human epithelial cells

“…Moreover, JNK reportedly regulates actin cytoskeleton dynamics and organization of the membrane skeleton. The former effect has been linked to JNK-dependent modulation of different actin binding proteins, such as ezrin, drebrin, and filamin in epithelial cells [59, 77, 83]. The latter effect was manifested by JNK-dependent phosphorylation of adducins in tumor cells [84], and disorganization of cortical α-spectrin in cardiomyocytes [85].…”

InDrosophila, RhoGEF2 cooperates with activated Ras in tumorigenesis through a pathway involving Rho1–Rok–Myosin-II and JNK signalling

“…However, in lgl mutant clones in the EAD, blocking JNK enhances the clonal overgrowth and leads to loss of polarity and an invasive phenotype (Grzeschik et al, 2010), and blocking JNK in scrib mutant EAD clones does not prevent, but rather enhances, the impairment of the Hippo pathway (Doggett et al, 2011). Interestingly, a recent study has revealed that, in scrib − + Ras ACT tumours, JNK activation upregulates expression of an F-actin cross-linking protein, Filamin (Cher), which acts to inhibit the Hippo pathway to promote overgrowth (Külshammer and Uhlirova, 2012). Therefore, although RhoGEF2-Rho1 + Ras ACT -mediated tumorigenesis requires JNK activation for the block to differentiation and pupation, and to promote invasion, whether JNK can also have a role in cell morphology changes or promoting proliferation via inhibition of the Hippo pathway in these tumours requires further investigation.…”

“…Whether these mechanisms contribute to the tumour growth of RhoGEF2–Rho1–Rok–Myosin-II with activated Ras in Drosophila epithelial tissues will require further analysis. Interestingly, a recent study revealed that Drosophila Filamin (Cher) binds to Myosin II and is important for activation of Myosin II activity in scrib − + Ras ACT tumours, and also that Myosin II activity is important for tumour overgrowth, via Hippo pathway inactivation, as well as invasion (Külshammer and Uhlirova, 2012). Thus, the cooperation of cell polarity mutants with oncogenic Ras might also require the RhoGEF2–Rho1–Rok–Myosin-II pathway.…”