Deregulated protein kinase A signaling and myospryn expression in muscular dystrophy.
Alterations in signaling pathway activity have been implicated in the pathogenesis of Duchenne muscular dystrophy, a degenerative muscle disease caused by a deficiency in the costameric protein dystrophin. Accordingly, the notion of the dystrophin-glycoprotein complex, and by extension the costamere, as harboring signaling components has received increased attention in recent years. The localization of most, if not all, signaling enzymes to this subcellular region relies on interactions with scaffolding proteins directly or indirectly associated with the dystrophin-glycoprotein complex. One of these scaffolds is myospryn, a large, muscle-specific protein kinase A (PKA) anchoring protein or AKAP. Previous studies have demonstrated a dysregulation of myospryn expression in human Duchenne muscular dystrophy, suggesting a connection to the pathophysiology of the disorder. Here we report that dystrophic muscle exhibits reduced PKA activity resulting, in part, from severely mislocalized myospryn and the type II regulatory subunit (RIIalpha) of PKA. Furthermore, we show that myospryn and dystrophin coimmunoprecipitate in native muscle extracts and directly interact in vitro. Our findings reveal for the first time abnormalities in the PKA signal transduction pathway and myospryn regulation in dystrophin deficiency.
Reynolds
Joseph G
JG
Department of Biology, Program in Cell and Molecular Biology, Boston University, Boston, MA 02215, USA.
McCalmon
Sarah A
SA
Donaghey
Julie A
JA
Naya
Francisco J
FJ
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002522:Chlorocebus aethiops; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D016189:Dystrophin / Q000378:metabolism; D006614:Hindlimb / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018101:Mice, Inbred mdx; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009136:Muscular Dystrophies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D015398:Signal Transduction
D002352:Carrier Proteins; C484938:Cmya5 protein, mouse; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D016189:Dystrophin; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D017868:Cyclic AMP-Dependent Protein Kinases