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Abstract
Asymmetric localization of adenomatous polyposis coli (APC) to the ends of a subset of microtubules located in the leading edges is essential for the establishment of front-rear polarity during cell migration. APC is known to associate with microtubules in three ways: through interaction with the plus-end tracking protein EB1, direct binding through a C-terminal basic region, and through interaction with the plus-end motor kinesin-2. Here we report that the middle region of APC has a previously unidentified microtubule plus-end-targeting function, suggesting an additional microtubule-binding mode for APC. Through the same region, APC interacts with Nup358 (also called RanBP2), a microtubule-binding nucleoporin. Ectopic expression of the middle region of APC is sufficient to recruit endogenous Nup358 to the plus ends of microtubules. Furthermore, our results indicate that Nup358 cooperates with kinesin-2 to regulate the localization of APC to the cell cortex through a nuclear-transport-independent mechanism. Using RNA interference and a scratch-induced wound-healing assay we demonstrate that Nup358 functions in polarized cell migration. These results reveal a more active role for structural nucleoporins in regulating fundamental cellular processes than previously anticipated.
Highlights
The microtubule cytoskeleton plays pivotal roles in cell movement, intracellular trafficking, mitosis and cell polarity
adenomatous polyposis coli (APC) associates with Nup358 in vivo Immunoprecipitation of HEK293 cell lysate using Nup358 antibodies, followed by western blot analysis of APC, indicated that Nup358 interacts with APC in vivo (Fig. 1A)
Closer examination confirmed that Nup358 localized to individual microtubules that were positive for RFP-APC-FL near the cell periphery
Summary
The microtubule cytoskeleton plays pivotal roles in cell movement, intracellular trafficking, mitosis and cell polarity. Microtubules, which are polymers of α- and β-tubulin subunits, alternate stochastically between growth and shrinkage phases (Desai and Mitchison, 1997). These dynamic microtubules are transiently stabilized when captured by cellular structures including cell cortex and kinetochores. Such a remodeling of microtubule cytoskeleton is important for coordinating the polarization process that involves establishment and maintenance of distinct membrane domains, segregation and positioning of organelles, and targeted delivery of cell fate determinants (Gundersen, 2002). Its role in microtubule reorganization and cell polarity is not well understood
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