The mechanosensor Filamin A/Cheerio promotes tumourigenesis via specific interactions with components of the cell cortex

Abstract

Cancer development has been linked to aberrant sensing and interpretation of mechanical cues and force‐generating properties. Here, we show that upregulation of the actin crosslinking protein Cheerio (Cher), the fly ortholog of Filamin A (FLNA), and the conformation of its mechanosensitive region (MSR) are instrumental to the malignancy of polarity‐deficient, Ras‐driven tumours in Drosophila epithelia. We demonstrate that impaired growth and cytoskeletal contractility of tumours devoid of cher can be rescued by stimulating myosin activity. Profiling the Cher interactome in tumour‐bearing imaginal discs identified several components of the cell cortex, including the β‐heavy Spectrin Karst (Kst), the scaffolding protein Big bang (Bbg), and 14‐3‐3ε. We show that Cher binds Bbg through the MSR while the interaction with 14‐3‐3ε and Kst is MSR‐independent. Importantly, our genetic studies define Bbg, Kst, and 14‐3‐3ε as tumour suppressors. The tumour‐promoting function of Cher thus relies on its capacity to control the contractile state of the cytoskeleton through interactions with myosin and specific components of the cell cortex.

Experience-dependent glial pruning of synaptic glomeruli during the critical period

“…1 C). Similar to Cheerio/FLNA roles in other cellular contexts 29 , 30 , we hypothesized Cheerio is required to properly regulate the glial actin cytoskeleton to enable projection infiltration phagocytosis. To test whether the glial F-actin cytoskeleton is restructured in response to critical period experience, we utilized the cell-targeted F-actin biomarker UAS-LifeAct::GFP 74 .…”

“…Four of these DNA binding sites regulated by the AP-1 repressor complex are situated directly upstream of the cheerio locus 29 . Cheerio is the Drosophila homolog of Filamin A (FLNA) that acts as a regulator of actin cytoskeleton dynamics via 1) F-actin cross-linking and 2) a scaffolding function that enables the actin cytoskeleton to respond appropriately to intracellular signaling 30 , 31 . F-actin remodeling is critical for dynamic extension of glial membrane projections during infiltration, engulfment, and phagocytosis 32 , 33 .…”

Filamin protects myofibrils from contractile damage through changes in its mechanosensory region

“…Apart from muscles, filamin is required for a variety of processes including the formation of ring canals in the nurse cells of the ovary [13], providing mechanical protection to nephrocytes [43], promoting macrophage infiltration during development [44], coordinating axon guidance in neurons [45], positioning the nucleus in nurse cells [46], and during epithelial tumor growth [47]. Because filamin function is linked to its binding partners, which are probably tissue-specific, we expect our domains to help interrogate filamin functions in other tissues.…”