AKAP12

Identity

Other names	Gravin
	SSeCKS
	AKAP250
	DKFZp686M0430
	DKFZp686O0331
HGNC	AKAP12
Location	6q25
	AKAP12 (6q24-25.2) in normal cells probed with a about 5Kb human AKAP12 probe. Courtesy of Irwin Gelman; adapted from Xia et al., Cancer Res.61:5644-5651, 2001.

DNA/RNA

Note	The AKAP12 gene is strongly conserved from fish to humans, including syntenic regions conserved in the mouse (chrom. 10) and rat (chrom. 1).
	Human and mouse cells have similar exon/intron usage and spacing. AKAP12 has three independent promoters, alpha, beta, and gamma. The gamma promoter is active only in the testes while the alpha and beta are co-active in most cells and tissues studied. Exons 1A1 and 1A2 combine to then splice to a common splice acceptor on Exon 2 used by Exon 1B. Exons 1A1 and 1A2 produce the N-terminal 103 amino acids of "AKAP12alpha" whereas Exon 1B encodes the N-terminal 8 amino acids of "AKAP12beta"; the remaining amino acids are encoded in Exon 2. "AKAP12gamma" is encoded by a read-through transcript starting in the intron upstream of Exon 2, utilizing an in-frame ATG in Exon 2. Therefore, the alpha, beta, and gamma transcripts encode proteins that only differ in their N-termini.
Pseudogene	None.

Protein

	A: Except for testes, most cells express four major isoforms of AKAP12 protein. The 305 kDa isoforms is the myristylated AKAP12alpha whereas the 287 kDa isoforms is AKAP12beta. The 250 kDa and 43 kDa isoforms are proteolytic cleavage products common to the AKAP12alpha and beta isoforms. B: Human AKAP12alpha encodes a 1,780 amino acids full-length protein. The first about 1,000 amino acids of human and rodent AKAP12 share 83% identity followed by about 600 amino acids with less than 20% identity. The N-terminal homology domain (green) shows about 40% identity to the Xgl (Xenopus gravin-like) gene in Xenopus. Both human and rodent AKAP12 share a shorter C-terminal domain containing the PKA-RII binding (AKAP) domain (green box in human AKAP12).

Expression	AKAP12 isoforms are expressed in most tissue and organ types, with high expression levels in the testes, ovary, brain, lung and heart. Most mesenchyme, smooth muscle and some epithelial cells (breast, prostate, lung, ovary) express significant AKAP12 levels. Lower levels of AKAP12 are found in endothelial cells, although express in these cells is usually associated with wounding and/or inflammation.
Localisation	Most cell types display a cortical cytoskeletal staining pattern for AKAP12, with enrichment at the plasma membrane (presumably, the myristylated isoforms) and in the perinucleus. However, some staining has been observed in cell nuclei, probably directed by 4 SV40 Tag-like nuclear localization signals (NLS) found in the N-terminal third of the protein.
Function	1) Facilitates the sensitization/resensitization reaction of beta-adrenergic receptors. 2) Scaffolds protein kinase (PK) A and PKC. 3) Autoantigen in some cases of myasthenia gravis. 4) Anti-angiogenic factor. The rodent orthologue has been shown to inhibit brain angiogenesis and induce the blood-brain barrier, and to inhibit VEGF-mediated metastasis. 5) Potential tumor suppressor. The rodent orthologue has been shown to suppress Src- and Ras-induced oncogenic proliferation in vitro and metastatic potential in vivo.
Homology	Southern blotting analysis as well as analysis of sequenced genomes indicates that vertebrates encode single AKAP12 orthologues, with no gene family members. Thus, the protein diversity of this gene stems from promoter choice, alternative splicing, proteolytic maturation and post-translational modification. AKAP12 has limited sequence homology based on short domains. For example, the C-terminal AKAP domain is homologous to the analogous domain in AKP79. Also, AKAP12 shares some so-called MARCKS protein-like effector domains- positively charged stretches of amino acids involved in plasma membrane targeting.

Mutations

Note	No known mutations are associated with AKAP12. However, there are at least 539 single nucleotide polymorphisms (SNP) as described.

External links

	Nomenclature
HGNC	AKAP12   370
Entrez_Gene	AKAP12  9590  A kinase (PRKA) anchor protein (gravin) 12
	Cards
Atlas	AKAP12ID607ch6q25
GeneCards	AKAP12
Ensembl	AKAP12 [Search_View]   ENSG00000131016 [Gene_View]
Genatlas	AKAP12
GeneLynx	AKAP12
eGenome	AKAP12
euGene	9590
	Genomic and cartography
GoldenPath	AKAP12  -  6q25   chr6:151603202-151719602 +  6q24-q25   [Description]    (hg18-Mar_2006)
Ensembl	AKAP12 - 6q24-q25 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	AKAP12
	Gene and transcription
Genbank	AB003476 [ ENTREZ ]
Genbank	AB210003 [ ENTREZ ]
Genbank	AF001504 [ ENTREZ ]
Genbank	AF086250 [ ENTREZ ]
Genbank	AK307578 [ ENTREZ ]
RefSeq	NM_005100 [ SRS ]    NM_005100 [ ENTREZ ]
RefSeq	NM_144497 [ SRS ]    NM_144497 [ ENTREZ ]
RefSeq	AC_000049 [ SRS ]    AC_000049 [ ENTREZ ]
RefSeq	AC_000138 [ SRS ]    AC_000138 [ ENTREZ ]
RefSeq	NC_000006 [ SRS ]    NC_000006 [ ENTREZ ]
RefSeq	NT_025741 [ SRS ]    NT_025741 [ ENTREZ ]
RefSeq	NW_001838990 [ SRS ]    NW_001838990 [ ENTREZ ]
RefSeq	NW_923184 [ SRS ]    NW_923184 [ ENTREZ ]
AceView	AKAP12 AceView - NCBI
Unigene	Hs.371240 [ SRS ]    Hs.371240 [ NCBI ]     HS371240 [ spliceNest ]
Fast-db	16810 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	Q02952 [ SRS]    Q02952 [ EXPASY ]     Q02952 [ INTERPRO ]     Q02952 [ UNIPROT ]
Interpro	IPR001573 PkinA_anch [ SRS ]    IPR001573 PkinA_anch [ EBI ]
CluSTr	Q02952
Pfam	PF03832 PkinA_anch [ SRS ]    PF03832 PkinA_anch [ Sanger ]    pfam03832 [ NCBI-CDD ]
Blocks	Q02952
HPRD	05263
	Protein Interaction databases
DIP	Q02952
IntAct	Q02952
	Polymorphism : SNP, mutations, diseases
OMIM	604698    [ map ]
GENECLINICS	604698
SNP	AKAP12 [dbSNP-NCBI]
SNP	NM_005100 [SNP-NCI]
SNP	NM_144497 [SNP-NCI]
SNP	AKAP12 [GeneSNPs - Utah]  AKAP12] [HGBASE - SRS]
HAPMAP	AKAP12 [HAPMAP]
COSMIC	AKAP12 [Somatic mutation (COSMIC-CGP-Sanger)]
HGMD	AKAP12
	General knowledge
Family Browser	AKAP12 [UCSC Family Browser]
SOURCE	NM_005100
SOURCE	NM_144497
SMD	Hs.371240
SAGE	Hs.371240
GO	cytoplasm [Amigo]  cytoplasm
GO	cytoskeleton [Amigo]  cytoskeleton
GO	protein targeting [Amigo]  protein targeting
GO	signal transduction [Amigo]  signal transduction
GO	G-protein coupled receptor protein signaling pathway [Amigo]  G-protein coupled receptor protein signaling pathway
GO	protein kinase A binding [Amigo]  protein kinase A binding
PubGene	AKAP12
TreeFam	AKAP12
CTD	9590 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	AKAP12 Related clones (RZPD - Berlin)
	PubMed
PubMed	27 Pubmed reference(s) in LocusLink

Bibliography

Molecular cloning and preliminary characterization of a novel cytoplasmic antigen recognized by myasthenia gravis sera.

Gordon T, Grove B, Loftus JC, O'Toole T, McMillan R, Lindstrom J, Ginsberg MH

The Journal of clinical investigation. 1992 ; 90 (3) : 992-999.

PMID 1522245

Gravin, an autoantigen recognized by serum from myasthenia gravis patients, is a kinase scaffold protein.

Nauert JB, Klauck TM, Langeberg LK, Scott JD

Current biology : CB. 1997 ; 7 (1) : 52-62.

PMID 9000000

Dynamic complexes of beta2-adrenergic receptors with protein kinases and phosphatases and the role of gravin.

Shih M, Lin F, Scott JD, Wang HY, Malbon CC

The Journal of biological chemistry. 1999 ; 274 (3) : 1588-1595.

PMID 9880537

The scaffold protein gravin (cAMP-dependent protein kinase-anchoring protein 250) binds the beta 2-adrenergic receptor via the receptor cytoplasmic Arg-329 to Leu-413 domain and provides a mobile scaffold during desensitization.

Fan G, Shumay E, Wang H, Malbon CC

The Journal of biological chemistry. 2001 ; 276 (26) : 24005-24014.

PMID 11309381

The role of SSeCKS/gravin/AKAP12 scaffolding proteins in the spaciotemporal control of signaling pathways in oncogenesis and development .

Gelman IH

Frontiers in bioscience : a journal and virtual library. 2002 ; 7 : d1782-d1797.

PMID 12133808

Low expression of the putative tumour suppressor gene gravin in chronic myeloid leukaemia, myelodysplastic syndromes and acute myeloid leukaemia.

Boultwood J, Pellagatti A, Watkins F, Campbell LJ, Esoof N, Cross NC, Eagleton H, Littlewood TJ, Fidler C, Wainscoat JS

British journal of haematology. 2004 ; 126 (4) : 508-511.

PMID 15287943

AKAP12/Gravin is inactivated by epigenetic mechanism in human gastric carcinoma and shows growth suppressor activity.

Choi MC, Jong HS, Kim TY, Song SH, Lee DS, Lee JW, Kim TY, Kim NK, Bang YJ

Oncogene. 2004 ; 23 (42) : 7095-7103.

PMID 15258566

Multiple promoters direct expression of three AKAP12 isoforms with distinct subcellular and tissue distribution profiles.

Streb JW, Kitchen CM, Gelman IH, Miano JM

The Journal of biological chemistry. 2004 ; 279 (53) : 56014-56023.

PMID 15496411

SSeCKS metastasis-suppressing activity in MatLyLu prostate cancer cells correlates with vascular endothelial growth factor inhibition.

Su B, Zheng Q, Vaughan MM, Bu Y, Gelman IH

Cancer research. 2006 ; 66 (11) : 5599-5607.

PMID 16740695

REVIEW articles	automatic search in PubMed
Last year publications	automatic search in PubMed

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Contributor(s)

Written	11-2006	Irwin H Gelman

Citation

This paper should be referenced as such :

Gelman IH . AKAP12. Atlas Genet Cytogenet Oncol Haematol. November 2006 . URL : http://AtlasGeneticsOncology.org/Genes/AKAP12ID607ch6q25.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Mon Aug 11 21:11:57 2008