title: Mitogen-activated protein kinase (MAPK/ERK) regulates adenomatous polyposis coli during growth-factor-induced cell extension.
abstract: 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.
authors.affiliation: Department of Biology, Stanford University, Stanford, CA 94305-5435,  USA.
authors.forename: Hector Y
authors.initials: HY
authors.lastname: Caro-Gonzalez
authors.forename: Lene N
authors.initials: LN
authors.lastname: Nejsum
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Siemers
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Shaler
authors.forename: W James
authors.initials: WJ
authors.lastname: Nelson
authors.forename: Angela I M
authors.initials: AI
authors.lastname: Barth
mesh_terms: D000199:Actins / Q000378:metabolism; D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism*; D000818:Animals; D022081:Cell Surface Extensions / Q000502:physiology*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D008870:Microtubules / Q000378:metabolism; D020932:Nerve Growth Factor / Q000378:metabolism; D016716:PC12 Cells; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering; D051381:Rats; D020703:ras GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000199:Actins; D025601:Adenomatous Polyposis Coli Protein; D003598:Cytoskeletal Proteins; C519154:IQGAP3 protein, rat; D034741:RNA, Small Interfering; D020703:ras GTPase-Activating Proteins; D020932:Nerve Growth Factor; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3