AKAP-Lbc: a molecular scaffold for the integration of cyclic AMP and Rho transduction pathways.
A Kinase-anchoring proteins (AKAPs) are a family of functionally related proteins involved in the targeting of the PKA holoenzyme towards specific physiological substrates. We have recently identified a novel anchoring protein expressed in cardiomyocytes, called AKAP-Lbc, that functions as a PKA-targeting protein as well as a guanine nucleotide exchange factor (GEF) that activates the GTPase RhoA. Here, we discuss the most recent findings elucidating the molecular mechanisms and the transduction pathways involved in the regulation of the AKAP-Lbc signaling complex inside cells. We could show that AKAP-Lbc is regulated in a bi-directional manner by signals that activate or deactivate its Rho-GEF activity. Activation of AKAP-Lbc occurs in response to agonists that stimulate G proteins coupled receptors linked to the heterotrimeric G protein G12, whereas inactivation occurs through mechanisms that require phosphorylation of AKAP-Lbc by anchored PKA and subsequent recruitment of the regulatory protein 14-3-3. Interestingly, we could demonstrate that AKAP-Lbc can form homo-oligomers inside cells and that 14-3-3 can inhibit the Rho-GEF activity of AKAP-Lbc only when the anchoring protein adopts an oligomeric conformation. These findings reveal the molecular architecture of the AKAP-Lbc transduction complex and provide a mechanistic explanation of how upstream signaling pathways can be integrated within the AKAP-Lbc transduction complex to precisely modulate the activation of Rho.
Diviani
Dario
D
Département de Pharmacologie et de Toxicologie, Faculté de Médecine, Rue du Bugnon 27, CH-1005 Lausanne, Switzerland. Dario.diviani@unil.ch
Baisamy
Laurent
L
Appert-Collin
Aline
A
D048948:14-3-3 Proteins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D046912:Multiprotein Complexes; D032383:Myocytes, Cardiac / Q000378:metabolism; D011108:Polymers / Q000378:metabolism; D015398:Signal Transduction; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
D048948:14-3-3 Proteins; D048868:Adaptor Proteins, Signal Transducing; D046912:Multiprotein Complexes; D011108:Polymers; C470173:ROPN1L protein, human; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D020741:rho GTP-Binding Proteins