title: Microtubule-associated proteins (MAPs) regulate cAMP signalling through exchange protein directly activated by cAMP (EPAC).
abstract: cAMP is an essential signalling molecule whose concentration in cells is regulated by a wide range of hormones. A large number of diseases, including cancer and asthma, are linked to improper regulation of the cAMP signalling system, and manipulation of cAMP levels by pharmaceutical agents has proven therapeutic benefit. The action of cAMP in cells is mediated through the signalling enzymes PKA (protein kinase A) and EPAC (exchange protein directly activated by cAMP). The study of the function of these proteins is essential to understand the role of cAMP in controlling disease. We have found that EPAC interacts with an ancillary protein, called LC2 (light chain 2), and this interaction enhances EPAC's ability to activate its substrate protein, Rap1 GTPase. This is an important finding because Rap1 is involved in the control of cell migration and cell shape, functions that are disrupted in diseases like cancer. LC2 appears to enhance EPAC activity towards Rap1 by increasing the ability of EPAC to interact with cAMP, so that EPAC activation occurs at lower concentrations of cAMP. The design of inhibitors that disrupt or enhance EPAC1-LC2 interaction may therefore form the basis of future therapeutics for diseases where cAMP signalling through Rap1 is improperly regulated.
authors.affiliation: Division of Biochemistry and Molecular Biology, IBLS (Institute of Biomedical and Life Sciences), Davidson Building, University of Glasgow, Glasgow G12 8QQ, UK. S.Yarwood@bio.gla.ac.uk
authors.forename: S J
authors.initials: SJ
authors.lastname: Yarwood
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D011485:Protein Binding; D015290:Second Messenger Systems / Q000502:physiology*; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism
chemical_list: D008869:Microtubule-Associated Proteins; D004917:Erythromycin; C057513:erythromycin propionate-N-acetylcysteinate; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D020827:rap1 GTP-Binding Proteins; D000111:Acetylcysteine