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The mechanosensor Filamin A/Cheerio promotes tumourigenesis via specific interactions with components of the cell cortex
Author(s) -
Külshammer Eva,
Kilinc Merve,
Csordás Gábor,
Bresser Tina,
Nolte Hendrik,
Uhlirova Mirka
Publication year - 2022
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.16408
Subject(s) - filamin , flna , microbiology and biotechnology , cytoskeleton , biology , myosin , actin , cell cortex , cell , genetics
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.