Anchorage-independent cell proliferation promoted by fascin's F-actin bundling
Isogai, T.; Murali, V. S.; Zhou, F.; Wang, X.; Rajendran, D.; Castro, L. P.; Venkateswaran, N.; Conacci-Sorrell, M.; Danuser, G.
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The actin filament (F-actin) bundling protein fascin-1 is highly enriched in many metastatic cancers. Fascins contribution to metastasis have been ascribed to its enhancement of cell migration and invasion. However, mouse genetic studies clearly point to functions also in tumorigenesis, yet without mechanistic underpinnings. Here, we show that fascin expression promotes the formation of a non-canonical signaling complex that enables anchorage-independent proliferation. This complex shares similarities to focal adhesions and we refer to them as pseudo-adhesion signaling scaffolds (PASS). PASS are enriched with tyrosine phosphorylated proteins and require fascins F-actin-bundling activity for its assembly. PASS serve as hubs for the Rac1/PAK/JNK proliferation signaling axis, driven by PASS-associated Rac-specific GEFs. Experimental disruption of either fascin or RacGEF function abrogates sustained proliferation of aggressive cancers in vitro and in vivo. These results add a new molecular element to the growing arsenal of metabolic and oncogenic signaling programs regulated by the cytoskeleton architecture.
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