AKAP13

A-kinase anchor protein 13 is an protein that in humans is encoded by the AKAP13 gene.[5][6][7] This protein is also called AKAP-Lbc because it encodes the lymphocyte blast crisis (Lbc) oncogene, and ARHGEF13/RhoGEF13 because it contains a guanine nucleotide exchange factor (GEF) domain for the RhoA small GTP-binding protein.

AKAP13
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2DRN, 2LG1, 4D0N, 4D0O
Identifiers
Aliases	AKAP13, A kinase (PRKA) anchor protein 13, AKAP-13, AKAP-Lbc, ARHGEF13, BRX, HA-3, Ht31, LBC, PRKA13, PROTO-LB, PROTO-LBC, c-lbc, p47, A-kinase anchoring protein 13, A-kinase anchor protein 13
External IDs	OMIM: 604686 MGI: 2676556 HomoloGene: 4903 GeneCards: AKAP13
Gene location (Human) Chr. Chromosome 15 (human)[1] Band 15q25.3 Start 85,380,571 bp[1] End 85,749,358 bp[1]
Gene location (Mouse) Chr. Chromosome 7 (mouse)[2] Band 7|7 D1 Start 75,455,534 bp[2] End 75,754,609 bp[2]
Gene ontology Molecular function • metal ion binding • MAP-kinase scaffold activity • Rho guanyl-nucleotide exchange factor activity • guanyl-nucleotide exchange factor activity • GO:0001948 protein binding • GO:0032947 molecular adaptor activity • protein kinase A binding • Rho GTPase binding • signal transducer activity • cAMP-dependent protein kinase activity Cellular component • membrane • cytosol • actin cytoskeleton • perinuclear region of cytoplasm • cell nucleus • cell cortex • actin filament • cortical actin cytoskeleton • cytoplasm • intracellular Biological process • regulation of cardiac muscle hypertrophy • bone development • GO:0007243 intracellular signal transduction • regulation of glucocorticoid mediated signaling pathway • positive regulation of Rho protein signal transduction • regulation of sarcomere organization • positive regulation of I-kappaB kinase/NF-kappaB signaling • adrenergic receptor signaling pathway • regulation of small GTPase mediated signal transduction • adrenergic receptor signaling pathway involved in heart process • heart development • positive regulation of apoptotic process • cardiac muscle cell differentiation • regulation of Rho protein signal transduction • protein phosphorylation • regulation of protein kinase activity • nuclear export • G-protein coupled receptor signaling pathway • positive regulation of MAP kinase activity • cell growth involved in cardiac muscle cell development Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	11214	75547
Ensembl	ENSG00000170776	ENSMUSG00000066406
UniProt	Q12802	E9Q394
RefSeq (mRNA)	NM_144767 NM_001270546 NM_006738 NM_007200	NM_029332
RefSeq (protein)	NP_001257475 NP_006729 NP_009131	NP_083608
Location (UCSC)	Chr 15: 85.38 – 85.75 Mb	Chr 7: 75.46 – 75.75 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Function

A-kinase anchor protein 13/Rho guanine nucleotide exchange factor 13 is guanine nucleotide exchange factor (GEF) for the RhoA small GTPase protein.[8][9] Rho is a small GTPase protein that is inactive when bound to the guanine nucleotide GDP. But when acted on by Rho GEF proteins such as AKAP13, this GDP is released and replaced by GTP, leading to the active state of Rho. In this active, GTP-bound conformation, Rho can bind to and activate specific effector proteins and enzymes to regulate cellular functions.[10] In particular, active Rho is a major regulator of the cell actin cytoskeleton.[10]

AKAP13 is a member of a group of four RhoGEF proteins known to be activated by G protein coupled receptors coupled to the G₁₂ and G₁₃ heterotrimeric G proteins.[8][9] The others are ARHGEF1 (also known as p115-RhoGEF), ARHGEF11 (also known as PDZ-RhoGEF), and ARHGEF12 (also known as LARG). [11][8] GPCR-regulated AKAP13 (and these related GEF proteins) acts as an effector for G₁₂ and G₁₃ G proteins. Unlike the other three members, AKAP13 does not function as RGS family GTPase-activating proteins (GAPs) to increase the rate of GTP hydrolysis of G₁₂/G₁₃ alpha proteins.[12]

The A-kinase anchor proteins (AKAPs) are a group of structurally diverse proteins that have the common function of binding to the regulatory subunit of protein kinase A (PKA), thus confining the holoenzyme to discrete locations within the cell. The AKAP13 gene encodes a member of the AKAP family since the protein binds tightly to PKA, especially in the heart.

Alternative splicing of this gene results in at least 3 transcript variants encoding different isoforms. All three contain the Dbl oncogene homology (DH) domain plus Pleckstrin homology (PH) domain (DH/PH domain) characteristic of Rho family GEFs, while only the longer two isoforms also contain the AKAP domain.[7] Therefore, these isoforms may function as scaffolding proteins to coordinate Rho signaling and protein kinase A signaling.

Interactions

AKAP13 has been shown to interact with:

• CTNNAL1[13]
• Estrogen receptor alpha[5]
• GNA12[9]
• GNA13[9]
• PRKAR2A[14][15]

See also

• Second messenger system
• G protein-coupled receptor
• Heterotrimeric G protein
• Small GTPases
• Rho family of GTPases
• Protein kinase A

References

1. GRCh38: Ensembl release 89: ENSG00000170776 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000066406 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Rubino D, Driggers P, Arbit D, Kemp L, Miller B, Coso O, et al. (May 1998). "Characterization of Brx, a novel Dbl family member that modulates estrogen receptor action". Oncogene. 16 (19): 2513–26. doi:10.1038/sj.onc.1201783. PMID 9627117.
6. Carr DW, Stofko-Hahn RE, Fraser ID, Bishop SM, Acott TS, Brennan RG, Scott JD (August 1991). "Interaction of the regulatory subunit (RII) of cAMP-dependent protein kinase with RII-anchoring proteins occurs through an amphipathic helix binding motif". The Journal of Biological Chemistry. 266 (22): 14188–92. PMID 1860836.
7. "Entrez Gene: AKAP13 A kinase (PRKA) anchor protein 13".
8. Diviani D, Soderling J, Scott JD (November 2001). "AKAP-Lbc anchors protein kinase A and nucleates Galpha 12-selective Rho-mediated stress fiber formation". The Journal of Biological Chemistry. 276 (47): 44247–57. doi:10.1074/jbc.M106629200. PMID 11546812.
9. Dutt P, Nguyen N, Toksoz D (February 2004). "Role of Lbc RhoGEF in Galpha12/13-induced signals to Rho GTPase". Cellular Signalling. 16 (2): 201–9. doi:10.1016/S0898-6568(03)00132-3. PMID 14636890.
10. Thumkeo D, Watanabe S, Narumiya S (Oct–Nov 2013). "Physiological roles of Rho and Rho effectors in mammals". European Journal of Cell Biology. 92 (10–11): 303–15. doi:10.1016/j.ejcb.2013.09.002. PMID 24183240.
11. Fukuhara S, Chikumi H, Gutkind JS (March 2001). "RGS-containing RhoGEFs: the missing link between transforming G proteins and Rho?". Oncogene. 20 (13): 1661–8. doi:10.1038/sj.onc.1204182. PMID 11313914.
12. Kozasa T (April 2001). "Regulation of G protein-mediated signal transduction by RGS proteins". Life Sciences. 68 (19–20): 2309–17. doi:10.1016/S0024-3205(01)01020-7. PMID 11358341.
13. Park B, Nguyen NT, Dutt P, Merdek KD, Bashar M, Sterpetti P, et al. (November 2002). "Association of Lbc Rho guanine nucleotide exchange factor with alpha-catenin-related protein, alpha-catulin/CTNNAL1, supports serum response factor activation". The Journal of Biological Chemistry. 277 (47): 45361–70. doi:10.1074/jbc.M202447200. PMID 12270917.
14. Alto NM, Soderling SH, Hoshi N, Langeberg LK, Fayos R, Jennings PA, Scott JD (April 2003). "Bioinformatic design of A-kinase anchoring protein-in silico: a potent and selective peptide antagonist of type II protein kinase A anchoring". Proceedings of the National Academy of Sciences of the United States of America. 100 (8): 4445–50. doi:10.1073/pnas.0330734100. PMC 153575. PMID 12672969.
15. Carr DW, Hausken ZE, Fraser ID, Stofko-Hahn RE, Scott JD (July 1992). "Association of the type II cAMP-dependent protein kinase with a human thyroid RII-anchoring protein. Cloning and characterization of the RII-binding domain". The Journal of Biological Chemistry. 267 (19): 13376–82. PMID 1618839.

External links

• Human AKAP13 genome location and AKAP13 gene details page in the UCSC Genome Browser.
• Overview of all the structural information available in the PDB for UniProt: Q12802 (A-kinase anchor protein 13) at the PDBe-KB.

Further reading

• Hausken ZE, Coghlan VM, Hastings CA, Reimann EM, Scott JD (September 1994). "Type II regulatory subunit (RII) of the cAMP-dependent protein kinase interaction with A-kinase anchor proteins requires isoleucines 3 and 5". The Journal of Biological Chemistry. 269 (39): 24245–51. PMID 7929081.
• Toksoz D, Williams DA (February 1994). "Novel human oncogene lbc detected by transfection with distinct homology regions to signal transduction products". Oncogene. 9 (2): 621–8. PMID 8290273.
• Sterpetti P, Hack AA, Bashar MP, Park B, Cheng SD, Knoll JH, et al. (February 1999). "Activation of the Lbc Rho exchange factor proto-oncogene by truncation of an extended C terminus that regulates transformation and targeting". Molecular and Cellular Biology. 19 (2): 1334–45. doi:10.1128/mcb.19.2.1334. PMC 116062. PMID 9891067.
• Sagi SA, Seasholtz TM, Kobiashvili M, Wilson BA, Toksoz D, Brown JH (May 2001). "Physical and functional interactions of Galphaq with Rho and its exchange factors". The Journal of Biological Chemistry. 276 (18): 15445–52. doi:10.1074/jbc.M008961200. PMC 1761691. PMID 11278452.
• Newlon MG, Roy M, Morikis D, Carr DW, Westphal R, Scott JD, Jennings PA (April 2001). "A novel mechanism of PKA anchoring revealed by solution structures of anchoring complexes". The EMBO Journal. 20 (7): 1651–62. doi:10.1093/emboj/20.7.1651. PMC 145475. PMID 11285229.
• Driggers PH, Segars JH, Rubino DM (December 2001). "The proto-oncoprotein Brx activates estrogen receptor beta by a p38 mitogen-activated protein kinase pathway". The Journal of Biological Chemistry. 276 (50): 46792–7. doi:10.1074/jbc.M106927200. PMC 4152864. PMID 11579095.
• Klussmann E, Edemir B, Pepperle B, Tamma G, Henn V, Klauschenz E, et al. (November 2001). "Ht31: the first protein kinase A anchoring protein to integrate protein kinase A and Rho signaling". FEBS Letters. 507 (3): 264–8. doi:10.1016/S0014-5793(01)02995-7. PMID 11696353.
• Tan YC, Wu H, Wang WN, Zheng Y, Wang ZX (November 2002). "Characterization of the interactions between the small GTPase RhoA and its guanine nucleotide exchange factors". Analytical Biochemistry. 310 (2): 156–62. doi:10.1016/S0003-2697(02)00382-2. PMID 12423633.
• Spierings E, Brickner AG, Caldwell JA, Zegveld S, Tatsis N, Blokland E, et al. (July 2003). "The minor histocompatibility antigen HA-3 arises from differential proteasome-mediated cleavage of the lymphoid blast crisis (Lbc) oncoprotein". Blood. 102 (2): 621–9. doi:10.1182/blood-2003-01-0260. PMID 12663445.
• Hornemann T, Kempa S, Himmel M, Hayess K, Fürst DO, Wallimann T (September 2003). "Muscle-type creatine kinase interacts with central domains of the M-band proteins myomesin and M-protein". Journal of Molecular Biology. 332 (4): 877–87. doi:10.1016/S0022-2836(03)00921-5. PMID 12972258.
• Chen LY, Zuraw BL, Ye RD, Pan ZK (February 2004). "A Rho exchange factor mediates fMet-Leu-Phe-induced NF-kappaB activation in human peripheral blood monocytes". The Journal of Biological Chemistry. 279 (8): 7208–12. doi:10.1074/jbc.M309542200. PMID 14660653.