Alternative titles; symbols
HGNC Approved Gene Symbol: AKAP12
Cytogenetic location: 6q25.1 Genomic coordinates (GRCh38) : 6:151,239,967-151,358,559 (from NCBI)
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.
By screening an endothelial cDNA expression library with serum from a myasthenia gravis (MG; 254200) patient, Gordon et al. (1992) isolated a partial cDNA encoding a 250-kD cytoplasmic protein, which the authors termed gravin. They found that gravin is expressed in endothelial cells, cultured fibroblasts, and osteosarcoma cells, but not in platelets, leukocytes, or monocytic cell lines. In erythroleukemic cell lines, gravin is expressed after phorbol ester induction. Indirect immunofluorescence of permeabilized cells revealed a trabecular network of gravin staining. Anti-gravin antibodies were present in the sera of 22 of 72 MG patients but were absent in the sera of 50 normal individuals and present in the sera of only 1 of 72 patients with other autoimmune diseases.
By screening fetal brain and adult heart cDNA libraries with radiolabeled regulatory (R) II subunit PKA as a probe, Nauert et al. (1997) isolated a cDNA fragment that showed sequence similarity to gravin. Using this fragment to screen a human heart cDNA library, they determined that gravin is a novel member of the AKAP family (AKAP12). The AKAP12 protein has 1,780 amino acids and contains an amphipathic alpha helix, the structure that binds RII, at residues 1540 to 1553. Binding studies with fragments of gravin confirmed the binding to RII and also determined that AKAP12 binds to and inhibits protein kinase C (PKC; see 176960) in a phosphatidylserine-dependent manner. Immunofluorescence and confocal microscopy of permeabilized cells showed that RII PKA and AKAP12 are colocalized at the cell periphery.
The International Radiation Hybrid Mapping Consortium assigned the AKAP12 gene to chromosome 6q24-q25 (stSG30260).
The blood-brain barrier is essential for maintaining brain homeostasis and low permeability. Both astrocytes and oxygen tension are believed to play a role in the development of the blood-brain barrier.
By use of cDNA representational difference analysis to identify blood-brain barrier maturation factors regulated by oxygen in astrocytes, Lee et al. (2003) found that expression of the rat gene SSeCKS (AKAP12), an ortholog of human gravin, was decreased by hypoxia and upregulated by reoxygenation at the transcriptional level. SSeCKS-overexpressing astrocytes decreased the expression of vascular endothelial growth factor (VEGF; 192240) via reduction of the AP1 transcription factor (165160), and stimulated expression of angiopoietin-1 (ANGPT1; 601667), an antipermeability factor in astrocytes, resulting in repression of angiogenesis in vitro and in vivo. SSeCKS increased the expression of tight junction proteins in endothelial cells. Lee et al. (2003) concluded that SSeCKS regulates blood-brain barrier differentiation by modulating both brain angiogenesis and tight junction formation.
Gordon, T., Grove, B., Loftus, J. C., O'Toole, T., McMillan, R., Lindstrom, J., Ginsberg, M. H. Molecular cloning and preliminary characterization of a novel cytoplasmic antigen recognized by myasthenia gravis sera. J. Clin. Invest. 90: 992-999, 1992. [PubMed: 1522245] [Full Text: https://doi.org/10.1172/JCI115976]
Lee, S.-W., Kim, W. J., Choi, Y. K., Song, H. S., Son, M. J., Gelman, I. H., Kim, Y.-J., Kim, K.-W. SSeCKS regulates angiogenesis and tight junction formation in blood-brain barrier. Nature Med. 9: 900-906, 2003. [PubMed: 12808449] [Full Text: https://doi.org/10.1038/nm889]
Nauert, J. B., Klauck, T. M., Langeberg, L. K., Scott, J. D. Gravin, an autoantigen recognized by serum from myasthenia gravis patients, is a kinase scaffold protein. Curr. Biol. 7: 52-62, 1997. [PubMed: 9000000] [Full Text: https://doi.org/10.1016/s0960-9822(06)00027-3]