AKAP13 explained

A-kinase anchor protein 13 is a protein that in humans, is encoded by the AKAP13 gene.^{[1] [2] [3]} 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.

Function

A-kinase anchor protein 13/Rho guanine nucleotide exchange factor 13 is guanine nucleotide exchange factor (GEF) for the RhoA small GTPase protein.^{[4] [5]} 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.^[6] In particular, active Rho is a major regulator of the cell actin cytoskeleton.^[6]

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.^{[4] [5]} The others are ARHGEF1 (also known as p115-RhoGEF), ARHGEF11 (also known as PDZ-RhoGEF), and ARHGEF12 (also known as LARG). ^{[7] [4]} 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.^[8]

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.^[3] 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^[9]
  • Estrogen receptor alpha GNA12^[5]
• GNA13^[5]
• PRKAR2A^{[10] [11]}

See also

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

Further reading

• Hausken ZE, Coghlan VM, Hastings CA, Reimann EM, Scott JD . 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 . September 1994 . 10.1016/S0021-9258(19)51074-2 . 7929081 . free .
• Toksoz D, Williams DA . Novel human oncogene lbc detected by transfection with distinct homology regions to signal transduction products . Oncogene . 9 . 2 . 621–8 . February 1994 . 8290273 .
• Sterpetti P, Hack AA, Bashar MP, Park B, Cheng SD, Knoll JH, Urano T, Feig LA, Toksoz D . 6 . 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 . February 1999 . 9891067 . 116062 . 10.1128/mcb.19.2.1334 .
• Sagi SA, Seasholtz TM, Kobiashvili M, Wilson BA, Toksoz D, Brown JH . Physical and functional interactions of Galphaq with Rho and its exchange factors . The Journal of Biological Chemistry . 276 . 18 . 15445–52 . May 2001 . 11278452 . 1761691 . 10.1074/jbc.M008961200 . free .
• Newlon MG, Roy M, Morikis D, Carr DW, Westphal R, Scott JD, Jennings PA . A novel mechanism of PKA anchoring revealed by solution structures of anchoring complexes . The EMBO Journal . 20 . 7 . 1651–62 . April 2001 . 11285229 . 145475 . 10.1093/emboj/20.7.1651 .
• Driggers PH, Segars JH, Rubino DM . 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 . December 2001 . 11579095 . 4152864 . 10.1074/jbc.M106927200 . free .
• Klussmann E, Edemir B, Pepperle B, Tamma G, Henn V, Klauschenz E, Hundsrucker C, Maric K, Rosenthal W . 6 . Ht31: the first protein kinase A anchoring protein to integrate protein kinase A and Rho signaling . FEBS Letters . 507 . 3 . 264–8 . November 2001 . 11696353 . 10.1016/S0014-5793(01)02995-7 . free .
• Tan YC, Wu H, Wang WN, Zheng Y, Wang ZX . Characterization of the interactions between the small GTPase RhoA and its guanine nucleotide exchange factors . Analytical Biochemistry . 310 . 2 . 156–62 . November 2002 . 12423633 . 10.1016/S0003-2697(02)00382-2 .
• Spierings E, Brickner AG, Caldwell JA, Zegveld S, Tatsis N, Blokland E, Pool J, Pierce RA, Mollah S, Shabanowitz J, Eisenlohr LC, van Veelen P, Ossendorp F, Hunt DF, Goulmy E, Engelhard VH . 6 . The minor histocompatibility antigen HA-3 arises from differential proteasome-mediated cleavage of the lymphoid blast crisis (Lbc) oncoprotein . Blood . 102 . 2 . 621–9 . July 2003 . 12663445 . 10.1182/blood-2003-01-0260 . 17864975 .
• Hornemann T, Kempa S, Himmel M, Hayess K, Fürst DO, Wallimann T . 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 . September 2003 . 12972258 . 10.1016/S0022-2836(03)00921-5 .
• Chen LY, Zuraw BL, Ye RD, Pan ZK . 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 . February 2004 . 14660653 . 10.1074/jbc.M309542200 . free .

Notes and References

1. Rubino D, Driggers P, Arbit D, Kemp L, Miller B, Coso O, Pagliai K, Gray K, Gutkind S, Segars J . 6 . Characterization of Brx, a novel Dbl family member that modulates estrogen receptor action . Oncogene . 16 . 19 . 2513–26 . May 1998 . 9627117 . 10.1038/sj.onc.1201783 . 20906586 .
2. Carr DW, Stofko-Hahn RE, Fraser ID, Bishop SM, Acott TS, Brennan RG, Scott JD . 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 . August 1991 . 10.1016/S0021-9258(18)98665-5 . 1860836 . free .
3. Web site: Entrez Gene: AKAP13 A kinase (PRKA) anchor protein 13.
4. Diviani D, Soderling J, Scott JD . 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 . November 2001 . 11546812 . 10.1074/jbc.M106629200 . free .
5. Dutt P, Nguyen N, Toksoz D . Role of Lbc RhoGEF in Galpha12/13-induced signals to Rho GTPase . Cellular Signalling . 16 . 2 . 201–9 . February 2004 . 14636890 . 10.1016/S0898-6568(03)00132-3 .
6. Thumkeo D, Watanabe S, Narumiya S . Physiological roles of Rho and Rho effectors in mammals . European Journal of Cell Biology . 92 . 10–11 . 303–15 . Oct–Nov 2013 . 24183240 . 10.1016/j.ejcb.2013.09.002 .
7. Fukuhara S, Chikumi H, Gutkind JS . RGS-containing RhoGEFs: the missing link between transforming G proteins and Rho? . Oncogene . 20 . 13 . 1661–8 . March 2001 . 11313914 . 10.1038/sj.onc.1204182 . free .
8. Kozasa T . Regulation of G protein-mediated signal transduction by RGS proteins . Life Sciences . 68 . 19–20 . 2309–17 . April 2001 . 11358341 . 10.1016/S0024-3205(01)01020-7 .
9. Park B, Nguyen NT, Dutt P, Merdek KD, Bashar M, Sterpetti P, Tosolini A, Testa JR, Toksoz D . 6 . 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 . November 2002 . 12270917 . 10.1074/jbc.M202447200 . free .
10. Alto NM, Soderling SH, Hoshi N, Langeberg LK, Fayos R, Jennings PA, Scott JD . 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 . April 2003 . 12672969 . 153575 . 10.1073/pnas.0330734100 . 2003PNAS..100.4445A . free .
11. Carr DW, Hausken ZE, Fraser ID, Stofko-Hahn RE, Scott JD . 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 . July 1992 . 10.1016/S0021-9258(18)42221-1 . 1618839 . free .