The mAKAP signaling complex: integration of cAMP, calcium, and MAP kinase signaling pathways.
Following its production by adenylyl cyclases, the second messenger cAMP is in involved in pleiotrophic signal transduction. The effectors of cAMP include the cAMP-dependent protein kinase (PKA), the guanine nucleotide exchange factor Epac (exchange protein activated by cAMP), and cAMP-dependent ion channels. In turn, cAMP signaling is attenuated by phosphodiesterase-catalyzed degradation. The association of cAMP effectors and the enzymes that regulate cAMP concentration into signaling complexes helps to explain the differential signaling initiated by members of the G(s)-protein coupled receptor family. The signal transduction complex formed by the scaffold protein mAKAP (muscle A kinase-anchoring protein) at the nuclear envelope of both striated myocytes and neurons contains three cAMP-binding proteins, PKA, Epac1, and the phosphodiesterase PDE4D3. In addition, the mAKAP complex also contains components of the ERK5 MAP kinase signaling pathway, the calcium release channel ryanodine receptor and the phosphatases PP2A as well as calcineurin. Analysis of the mAKAP complex illustrates how a macromolecular complex can serve as a node in the intracellular signaling network of cardiac myocytes to integrate multiple cAMP signals with those of calcium and MAP kinases to regulate the hypertrophic actions of several hormones.
Dodge-Kafka
Kimberly L
KL
Pat and Jim Calhoun Center for Cardiology, University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT 06030, USA. dodge@uchc.edu
Kapiloff
Michael S
MS
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism; D054758:A Kinase Anchor Proteins; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism* / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D006332:Cardiomegaly / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D006801:Humans; D048671:MAP Kinase Kinase 5 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D032342:Muscle Cells / Q000378:metabolism; D009685:Nuclear Envelope / Q000378:metabolism; D020239:Receptor Cross-Talk; D015398:Signal Transduction
D054758:A Kinase Anchor Proteins; D048868:Adaptor Proteins, Signal Transducing; C484293:Akap6 protein, rat; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D048671:MAP Kinase Kinase 5; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D002118:Calcium