APC Is an RNA-Binding Protein, and Its Interactome Provides a Link to Neural Development and Microtubule Assembly

Abstract

SUMMARY Adenomatous polyposis coli (APC) is a microtubule plus-end scaffolding protein important in biology and disease. APC is implicated in RNA localization, although the mechanisms and functional significance remain unclear. We show that APC is an RNA-binding protein, and identify an RNA interactome by HITS-CLIP. Targets were highly enriched for APC-related functions, including microtubule organization, cell motility, cancer and neurologic disease. Among the targets is β2B-tubulin, known to be required in human neuron and axon migration. We show β2B-tubulin is synthesized in axons and localizes preferentially to dynamic microtubules in the growth cone periphery. APC binds the β2B-tubulin 3'UTR; treatments interfering with this interaction reduced β2B-tubulin mRNA axonal localization and expression, depleted dynamic microtubules and the growth cone periphery, and impaired neuron migration. These results identify APC as a platform binding functionally-related protein and RNA networks, and suggest a self-organizing model for the microtubule to localize synthesis of its own subunits.

Canonical and noncanonical Wnt signaling in neural stem/progenitor cells

“…However, it is worth noting that while LiCl and APC gene deletion both activate β-catenin signaling, these treatments have unrelated β-catenin-independent effects [135][136][137][138]. APC, for example, also plays a role in neuronal migration by binding the 3′ UTR of β2B-tubulin mRNA [139].…”

Targeting Axonal Protein Synthesis in Neuroregeneration and Degeneration

“…Only at the beginning of this century did work by Holt's group conclusively demonstrate that local protein synthesis is required for the chemotropic responses of axons to attractive and repulsive guidance cues [7]. This work heralded an extremely productive phase of research on local translation in developing axons, and now intra-axonal protein synthesis is recognized to be crucial for growth cone behavior [7][8][9][10][11][12][13][14], axonal pathfinding [15][16][17], axon maintenance [18], and retrograde signaling in developing axons [19,20]. However, far less is known about the extent and importance of localized protein synthesis in axons after the developmental period.…”

Proteomic analysis reveals APC-dependent post translational modifications and identifies a novel regulator of β-catenin

“…Disruption of these functions has negative consequences, including decreased cell migration and differentiation, chromosomal instability, and increased proliferation that may contribute to cancer initiation and progression (Nathke, 2004(Nathke, , 2006. Furthermore, new APC protein domains are still being identified, which in turn are uncovering new protein and pathway interactions that might also contribute (Zhang et al, 2010;Kunttas-Tatli et al, 2014;Preitner et al, 2014).…”