The mAKAPbeta scaffold regulates cardiac myocyte hypertrophy via recruitment of activated calcineurin.
mAKAPbeta is the scaffold for a multimolecular signaling complex in cardiac myocytes that is required for the induction of neonatal myocyte hypertrophy. We now show that the pro-hypertrophic phosphatase calcineurin binds directly to a single site on mAKAPbeta that does not conform to any of the previously reported consensus binding sites. Calcineurin-mAKAPbeta complex formation is increased in the presence of Ca(2+)/calmodulin and in norepinephrine-stimulated primary cardiac myocytes. This binding is of functional significance because myocytes exhibit diminished norepinephrine-stimulated hypertrophy when expressing a mAKAPbeta mutant incapable of binding calcineurin. In addition to calcineurin, the transcription factor NFATc3 also associates with the mAKAPbeta scaffold in myocytes. Calcineurin bound to mAKAPbeta can dephosphorylate NFATc3 in myocytes, and expression of mAKAPbeta is required for NFAT transcriptional activity. Taken together, our results reveal the importance of regulated calcineurin binding to mAKAPbeta for the induction of cardiac myocyte hypertrophy. Furthermore, these data illustrate how scaffold proteins organizing localized signaling complexes provide the molecular architecture for signal transduction networks regulating key cellular processes.
Li
Jinliang
J
Department of Pediatrics and Medicine, University of Miami Miller School of Medicine, Cardiac Signal Transduction and Cellular Biology Laboratory, Interdisciplinary Stem Cell Institute, Miami, FL 33101, USA.
Negro
Alejandra
A
Lopez
Johanna
J
Bauman
Andrea L
AL
Henson
Edward
E
Dodge-Kafka
Kimberly
K
Kapiloff
Michael S
MS
D054758:A Kinase Anchor Proteins / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism; D006332:Cardiomegaly / Q000201:enzymology*; D002460:Cell Line; D004789:Enzyme Activation; D006801:Humans; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology*; D050778:NFATC Transcription Factors / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley
D054758:A Kinase Anchor Proteins; C484293:Akap6 protein, rat; D002147:Calmodulin; D050778:NFATC Transcription Factors; D019703:Calcineurin; D002118:Calcium