title: Impaired dynamin 2 function leads to increased AP-1 transcriptional activity through the JNK/c-Jun pathway.
abstract: Activation of AP-1 transcription factors, composed of the Jun and Fos proteins, regulates cellular fates, such as proliferation, differentiation or apoptosis. Among other stimuli, the AP-1 pathway can be initiated by extracellular ligands, such as growth factors or cytokines, which undergo internalization in complex with their receptors. Endocytosis has been implicated in the regulation of several signaling pathways; however its possible impact on AP-1 signaling remains unknown. Here we show that inhibition of dynamin 2 (Dyn2), a major regulator of endocytic internalization, strongly stimulates the AP-1 pathway. Specifically, expression of a dominant-negative Dyn2 K44A mutant increases the total levels of c-Jun, its phosphorylation on Ser63/73 and transcription of AP-1 target genes. Interestingly, DNM2 mutations implicated in human neurological disorders exhibit similar effects on AP-1 signaling. Mechanistically, Dyn2 K44A induces AP-1 by increasing phosphorylation of several receptor tyrosine kinases. Their activation is required to initiate a Src- and JNK-dependent signaling cascade converging on c-Jun and stimulating expression of AP-1 target genes. Cumulatively, our data uncover a link between the Dyn2 function and JNK signaling which leads to AP-1 induction.
authors.affiliation: Laboratory of Cell Biology, International Institute of Molecular and Cell Biology, Warsaw, Poland.
authors.forename: Ewelina
authors.initials: E
authors.lastname: Szymanska
authors.affiliation: Laboratory of Cell Biology, International Institute of Molecular and Cell Biology, Warsaw, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Skowronek
authors.affiliation: Laboratory of Cell Biology, International Institute of Molecular and Cell Biology, Warsaw, Poland. Electronic address: miaczynska@iimcb.gov.pl.
authors.forename: Marta
authors.initials: M
authors.lastname: Miaczynska
mesh_terms: D002478:Cells, Cultured; D034285:Dynamin II / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D048031:JNK Mitogen-Activated Protein Kinases; D034285:Dynamin II
keywords: AP-1; Dynamin; Receptor tyrosine kinases; c-Jun