Spatial restriction of PDK1 activation cascades by anchoring to mAKAPalpha.
The muscle A-kinase anchoring protein (mAKAP) tethers cAMP-dependent enzymes to perinuclear membranes of cardiomyocytes. We now demonstrate that two alternatively spliced forms of mAKAP are expressed: mAKAPalpha and mAKAPbeta. The longer form, mAKAPalpha, is preferentially expressed in the brain. mAKAPbeta is a shorter form of the anchoring protein that lacks the first 244 amino acids and is preferentially expressed in the heart. The unique amino terminus of mAKAPalpha can spatially restrict the activity of 3-phosphoinositide-dependent kinase-1 (PDK1). Biochemical and genetic analyses demonstrate that simultaneous recruitment of PDK1 and ERK onto mAKAPalpha facilitates activation and release of the downstream target p90RSK. The assembly of tissue-specific signaling complexes provides an efficient mechanism to integrate and relay lipid-mediated and mitogenic activated signals to the nucleus.
Michel
Jennifer J Carlisle
JJ
Howard Hughes Medical Institute and Vollum Institute, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, Oregon 97239, USA.
Townley
Ian K
IK
Dodge-Kafka
Kimberly L
KL
Zhang
Fang
F
Kapiloff
Michael S
MS
Scott
John D
JD
D064413:3-Phosphoinositide-Dependent Protein Kinases; D054758:A Kinase Anchor Proteins; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism*; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D003001:Cloning, Molecular; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009928:Organ Specificity / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism
D054758:A Kinase Anchor Proteins; D048868:Adaptor Proteins, Signal Transducing; C484293:Akap6 protein, rat; D012333:RNA, Messenger; C507157:mAkap6 protein, mouse; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578562:PDPK1 protein, human; C578564:Pdpk1 protein, mouse; C578579:Pdpk1 protein, rat; D017346:Protein Serine-Threonine Kinases; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D048049:Extracellular Signal-Regulated MAP Kinases