Alternative titles; symbols
A-KINASE ANCHOR PROTEIN, 100-KD; AKAP100
Gene map locus
14q
TEXT
A-kinase anchor proteins (AKAPs; see 602449) direct the activity of protein kinase A (PKA; see 176911) by tethering the enzyme near its physiologic substrates.
CLONING
By screening hippocampal and fetal brain cDNA libraries for PKA type II regulatory (RII) subunit anchoring proteins, McCartney et al. (1995) obtained a cDNA encoding a novel AKAP protein, AKAP6, which the authors designated AKAP100. The AKAP6 protein contains 655 amino acids. Helical wheel analysis revealed the presence of an amphipathic helix similar to that in other AKAPs. Northern blot analysis revealed expression of a single transcript of 8 kb, with highest expression in cardiac and skeletal muscle. Expression was also present in certain areas of the brain, including cerebellum, basal ganglia, hippocampus, frontal cortex, and motor cortex. Western blot analysis and autoradiography demonstrated that AKAP6 binds RII-alpha (176910). By fluorescence and confocal microscopy in a cardiac muscle cell line, McCartney et al. (1995) showed that AKAP6 and RII are localized in the sarcoplasmic reticulum. Using affinity chromatography on cAMP agarose and Western blots, McCartney et al. (1995) showed that AKAP100 copurified with RII in cell lysates. 
Analysis by Kapiloff et al. (1999) revealed that the 5-prime end of the original AKAP100 cDNA was rearranged, thereby introducing an in-frame stop codon. By multiple rounds of 5-prime RACE, they obtained a full-length cDNA encoding AKAP6, which they called mAKAP (muscle AKAP). The deduced 2,319-amino acid AKAP6 protein shares 79% amino acid identity with rat mAkap. Western blot analysis showed expression of an approximately 300-kD protein in heart. Immunofluorescence analysis indicated that AKAP6 is localized at the nuclear membrane, and most likely not at the sarcoplasmic reticulum, in heart tissue. Nuclear membrane targeting is conferred by 2 regions of the AKAP6 protein, residues 772 to 915 and 915 to 1,065, that contain spectrin-like repeat sequences.
GENE FUNCTION
Dodge-Kafka et al. (2005) identified a cAMP-responsive signaling complex maintained by the muscle-specific A-kinase anchoring protein (AKAP6) that includes PKA (188830), PDE4D3 (600129), and EPAC1 (606057). 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 AKAP6-associated ERK5 (602521) kinase module suppresses PDE4D3. PDE4D3 also functions as an adaptor protein that recruits EPAC1, an exchange factor for the small GTPase RAP1 (179520), to enable cAMP-dependent attenuation of ERK5. Pharmacologic and molecular manipulations of the AKAP6 complex showed that anchored ERK5 can induce cardiomyocyte hypertrophy. Thus, Dodge-Kafka et al. (2005) concluded that 2 coupled cAMP-dependent feedback loops are coordinated within the context of the AKAP6 complex, suggesting that local control of cAMP signaling by AKAP proteins is more intricate than had been appreciated.
MAPPING
By radiation hybrid analysis, Nagase et al. (1997) mapped the AKAP6 gene, which they called KIAA0311, to chromosome 14. Kapiloff et al. (1999) identified 4 STS markers with sequences identical to regions of AKAP6, thereby mapping the AKAP6 gene to 14q. The authors noted that AKAP6 is localized to the same region as arrhythmogenic right ventricular dysplasia-1 (ARVD1; 107970).
REFERENCES
- 1. Dodge-Kafka, K. L.; Soughayer, J.; Pare, G. C.; Michel, J. J. C.; Langeberg, L. K.; Kapiloff, M. S.; Scott, J. D. :
- The protein kinase A anchoring protein mAKAP coordinates two integrated cAMP effector pathways. Nature 437: 574-578, 2005.
PubMed ID : 16177794
- 2. Kapiloff, M. S.; Schillace, R. V.; Westphal, A. M.; Scott, J. D. :
- mAKAP: an A-kinase anchoring protein targeted to the nuclear membrane of differentiated myocytes. J. Cell Sci. 112: 2725-2736, 1999.
PubMed ID : 10413680
- 3. McCartney, S.; Little, B. M.; Langeberg, L. K.; Scott, J. D. :
- Cloning and characterization of A-kinase anchor protein 100 (AKAP100): a protein that targets A-kinase to the sarcoplasmic reticulum. J. Biol. Chem. 270: 9327-9333, 1995.
PubMed ID : 7721854
- 4. Nagase, T.; Ishikawa, K.; Nakajima, D.; Ohira, M.; Seki, N.; Miyajima, N.; Tanaka, A.; Kotani, H.; Nomura, N.; Ohara, O. :
- Prediction of the coding sequences of unidentified human genes. VII. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res. 4: 141-150, 1997.
PubMed ID : 9205841
CONTRIBUTORS
Ada Hamosh - updated : 11/3/2005
Paul J. Converse - updated : 7/7/2000
CREATION DATE
Paul J. Converse : 3/17/2000
EDIT HISTORY
alopez : 11/7/2005
terry : 11/3/2005
mgross : 7/7/2000
carol : 3/17/2000
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