title: Spatial regulation of cyclic AMP-Epac1 signaling in cell adhesion by ERM proteins.
abstract: Epac1 is a guanine nucleotide exchange factor for the small G protein Rap and is involved in membrane-localized processes such as integrin-mediated cell adhesion and cell-cell junction formation. Cyclic AMP (cAMP) directly activates Epac1 by release of autoinhibition and in addition induces its translocation to the plasma membrane. Here, we show an additional mechanism of Epac1 recruitment, mediated by activated ezrin-radixin-moesin (ERM) proteins. Epac1 directly binds with its N-terminal 49 amino acids to ERM proteins in their open conformation. Receptor-induced activation of ERM proteins results in increased binding of Epac1 and consequently the clustered localization of Epac1 at the plasma membrane. Deletion of the N terminus of Epac1, as well as disruption of the Epac1-ERM interaction by an interfering radixin mutant or small interfering RNA (siRNA)-mediated depletion of the ERM proteins, impairs Epac1-mediated cell adhesion. We conclude that ERM proteins are involved in the spatial regulation of Epac1 and cooperate with cAMP- and Rap-mediated signaling to regulate adhesion to the extracellular matrix.
authors.affiliation: Department of Physiological Chemistry, Center for Biomedical Genetics, and Cancer Genomics Center, University Medical Center Utrecht, Utrecht, Netherlands.
authors.forename: Martijn
authors.initials: M
authors.lastname: Gloerich
authors.forename: Bas
authors.initials: B
authors.lastname: Ponsioen
authors.forename: Marjolein J
authors.initials: MJ
authors.lastname: Vliem
authors.forename: Zhongchun
authors.initials: Z
authors.lastname: Zhang
authors.forename: Jun
authors.initials: J
authors.lastname: Zhao
authors.forename: Matthijs R
authors.initials: MR
authors.lastname: Kooistra
authors.forename: Leo S
authors.initials: LS
authors.lastname: Price
authors.forename: Laila
authors.initials: L
authors.lastname: Ritsma
authors.forename: Fried J
authors.initials: FJ
authors.lastname: Zwartkruis
authors.forename: Holger
authors.initials: H
authors.lastname: Rehmann
authors.forename: Kees
authors.initials: K
authors.lastname: Jalink
authors.forename: Johannes L
authors.initials: JL
authors.lastname: Bos
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D020798:Two-Hybrid System Techniques; D020827:rap1 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000099149:Ezrin
chemical_list: D000242:Cyclic AMP; D003598:Cytoskeletal Proteins; D020662:Guanine Nucleotide Exchange Factors; D008565:Membrane Proteins; D008840:Microfilament Proteins; D043562:Receptors, G-Protein-Coupled; D011993:Recombinant Fusion Proteins; D020827:rap1 GTP-Binding Proteins; D000099149:Ezrin; C116122:RAPGEF3 protein, human; C442864:RAPGEF4 protein, human; C071058:moesin; C071776:radixin