Abstract
SummaryFilopodia are adhesive cellular protrusions specialized in the detection of extracellular matrix (ECM)-derived cues. Although ECM engagement at focal adhesions is known to trigger the recruitment of hundreds of proteins (“adhesome”) to fine-tune cellular behavior, the components of the filopodia adhesions remain undefined. Here, we performed a structured-illumination-microscopy-based screen to map the localization of 80 target proteins, linked to cell adhesion and migration, within myosin-X-induced filopodia. We demonstrate preferential enrichment of several adhesion proteins to either filopodia tips, filopodia shafts, or shaft subdomains, suggesting divergent, spatially restricted functions for these proteins. Moreover, proteins with phosphoinositide (PI) binding sites are particularly enriched in filopodia. This, together with the strong localization of PI(3,4)P2 in filopodia tips, predicts critical roles for PIs in regulating filopodia ultra-structure and function. Our mapping further reveals that filopodia adhesions consist of a unique set of proteins, the filopodome, that are distinct from classical nascent adhesions, focal adhesions, and fibrillar adhesions. Using live imaging, we observe that filopodia adhesions can give rise to nascent adhesions, which, in turn, form focal adhesions. We demonstrate that p130Cas (BCAR1) is recruited to filopodia tips via its C-terminal Cas family homology domain (CCHD) and acts as a mechanosensitive regulator of filopodia stability. Finally, we demonstrate that our map based on myosin-X-induced filopodia can be translated to endogenous filopodia and fascin- and IRSp53-mediated filopodia.
Highlights
The ability of cells to migrate in vivo is necessary for many physiological processes, including embryonic development, tissue homeostasis, and wound healing
Filopodia are adhesive cellular protrusions specialized in the detection of extracellular matrix (ECM)derived cues
ECM engagement at focal adhesions is known to trigger the recruitment of hundreds of proteins (‘‘adhesome’’) to fine-tune cellular behavior, the components of the filopodia adhesions remain undefined
Summary
The ability of cells to migrate in vivo is necessary for many physiological processes, including embryonic development, tissue homeostasis, and wound healing. Cells interact with their environment, the extracellular matrix (ECM), via adhesion receptors, such as integrins, which provide a physical link between the ECM and the actin cytoskeleton [1]. Integrin function is controlled by a conformational switch between active and inactive states that determines ECM ligand interaction and subsequent receptor signaling [2]. In 2D, integrin-ligand engagement leads to the assembly of large signaling platforms, termed focal adhesions (FAs), which are composed of hundreds of proteins collectively termed the adhesome [3, 4]. FAs provide anchorage and represent integrin heterodimer-ligand-specific [5] and/or ECM-ligand-specific signaling nodes with mechanosensing functions [6] and constitute ideal signaling platforms for ECM recognition
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