The protein kinase A anchoring protein mAKAP coordinates two integrated cAMP effector pathways.
Cyclic adenosine 3', 5'-monophosphate (cAMP) is a ubiquitous mediator of intracellular signalling events. It acts principally through stimulation of cAMP-dependent protein kinases (PKAs) but also activates certain ion channels and guanine nucleotide exchange factors (Epacs). Metabolism of cAMP is catalysed by phosphodiesterases (PDEs). Here we identify a cAMP-responsive signalling complex maintained by the muscle-specific A-kinase anchoring protein (mAKAP) that includes PKA, PDE4D3 and Epac1. These intermolecular interactions facilitate the dissemination of distinct cAMP signals through each effector protein. Anchored PKA stimulates PDE4D3 to reduce local cAMP concentrations, whereas an mAKAP-associated ERK5 kinase module suppresses PDE4D3. PDE4D3 also functions as an adaptor protein that recruits Epac1, an exchange factor for the small GTPase Rap1, to enable cAMP-dependent attenuation of ERK5. Pharmacological and molecular manipulations of the mAKAP complex show that anchored ERK5 can induce cardiomyocyte hypertrophy. Thus, two coupled cAMP-dependent feedback loops are coordinated within the context of the mAKAP complex, suggesting that local control of cAMP signalling by AKAP proteins is more intricate than previously appreciated.
Dodge-Kafka
Kimberly L
KL
Howard Hughes Medical Institute, Oregon Health and Sciences University, Portland, Oregon 97239, USA.
Soughayer
Joseph
J
Pare
Genevieve C
GC
Carlisle Michel
Jennifer J
JJ
Langeberg
Lorene K
LK
Kapiloff
Michael S
MS
Scott
John D
JD
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D016207:Cytokines / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D006984:Hypertrophy / Q000139:chemically induced; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism; D046912:Multiprotein Complexes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D051381:Rats; D015398:Signal Transduction
D016207:Cytokines; D020662:Guanine Nucleotide Exchange Factors; D046912:Multiprotein Complexes; C116122:RAPGEF3 protein, human; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D048054:Mitogen-Activated Protein Kinase 7; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4