Journal
JOURNAL OF CELL SCIENCE
Volume 125, Issue 5, Pages 1247-1258Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.095166
Keywords
Adenomatous polyposis coli (APC); MAPK/ERK; Cell extension; NGF; EGF; GSK-3 beta; Microtubules; Actin
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Funding
- National Institutes of Health [GM078270]
- Minority Supplement on Parent Grant [5R37-GM35527]
- Lundbeck Foundation
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Regulation of the microtubule- and actin-binding protein adenomatous polyposis coli (APC) is crucial for the formation of cell extensions in many cell types. This process requires inhibition of glycogen synthase kinase-3 beta (GSK-3 beta), which otherwise phosphorylates APC and decreases APC-mediated microtubule bundling. Although it is assumed, therefore, that APC phosphorylation is decreased during initiation of cell extensions, the phosphorylation state of APC has never been analyzed directly. We show here that NGF-and EGF-induced initial cell extensions result in APC phosphorylation by the MAPK/ERK pathway, which, in parallel with inhibition of GSK-3 beta, promotes localization of APC to the tip of cell extensions. Whereas GSK-3 beta inhibition promotes APC binding and stabilization of microtubules, we show that phosphorylation by ERK inhibits the interaction of APC with F-actin, and APC-mediated F-actin bundling, but not APC-mediated microtubule bundling, in vitro. These results identify a previously unknown APC regulatory pathway during growth-factor-induced cell extension, and indicate that the GSK-3 beta and ERK pathways act in parallel to regulate interactions between APC and the cytoskeleton during the formation of cell extensions.
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