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Mitogen-activated protein kinase (MAPK/ERK) regulates adenomatous polyposis coli during growth-factor-induced cell extension
Hector Y. Caro-Gonzalez, Lene N. Nejsum, Kathleen A. Siemers, Thomas A. Shaler, W. James Nelson, Angela I. M. Barth


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-3β (GSK-3β), 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-3β, promotes localization of APC to the tip of cell extensions. Whereas GSK-3β 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-3β and ERK pathways act in parallel to regulate interactions between APC and the cytoskeleton during the formation of cell extensions.


  • * These authors contributed equally to this work

  • Present address: Department of Molecular and Cellular Biology, University of California, Davis, CA 95616, USA

  • Present address: Department of Molecular Biology and Genetics and Interdisciplinary Nanoscience Center (iNANO), Aarhus University, 8000 Aarhus C, Denmark

  • § Present address: SRI International Molecular Physics Laboratory, 333 Ravenswood Ave, Menlo Park, CA 94025, USA

  • Funding

    This work was supported by the National Institutes of Health [grant number GM078270] to W.J.N.; a Minority Supplement on Parent Grant [grant number 5R37-GM35527] to H.Y.C.G.; and a postdoctoral fellowship from the Lundbeck Foundation to L.N.N. Deposited in PMC for release after 12 months.

  • Supplementary material available online at

  • Accepted October 10, 2011.
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