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Anchoring of both PKA and 14‐3‐3 inhibits the Rho‐GEF activity of the AKAP‐Lbc signaling complex
Author(s) -
Diviani Dario,
Abuin Liliane,
Cotecchia Susanna,
Pansier Laetitia
Publication year - 2004
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600287
Subject(s) - biology , anchoring , signal transduction , microbiology and biotechnology , biophysics , cognitive science , psychology
A‐kinase anchoring proteins (AKAPs) target the cAMP‐regulated protein kinase (PKA) to its physiological substrates. We recently identified a novel anchoring protein, called AKAP‐Lbc, which functions as a PKA‐targeting protein as well as a guanine nucleotide exchange factor (GEF) for RhoA. We demonstrated that AKAP‐Lbc Rho‐GEF activity is stimulated by the alpha subunit of the heterotrimeric G protein G12. Here, we identified 14‐3‐3 as a novel regulatory protein interacting with AKAP‐Lbc. Elevation of the cellular concentration of cAMP activates the PKA holoenzyme anchored to AKAP‐Lbc, which phosphorylates the anchoring protein on the serine 1565. This phosphorylation event induces the recruitment of 14‐3‐3, which inhibits the Rho‐GEF activity of AKAP‐Lbc. AKAP‐Lbc mutants that fail to interact with PKA or with 14‐3‐3 show a higher basal Rho‐GEF activity as compared to the wild‐type protein. This suggests that, under basal conditions, 14‐3‐3 maintains AKAP‐Lbc in an inactive state. Therefore, while it is known that AKAP‐Lbc activity can be stimulated by Gα12, in this study we demonstrated that it is inhibited by the anchoring of both PKA and 14‐3‐3.