Rho-Selective Guanine Exchange FactorAKAP13 Mediates Stress Fiber Formation

The A-kinase anchor protein 13 (AKAP13, also known as AKAP-LBC) is one of a group of structurally diverse proteins, which have the common function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. AKAP13 is a splice variant of the oncogene Lbc. Alternative splicing of the AKAP13 gene results in at least 3 transcript variants encoding different isoforms containing a Dbl oncogene homology (DH) domain and a pleckstrin homology (PH) domain. The DH domain is associated with guanine nucleotide exchange activation for the Rho/Rac family of small GTP binding proteins, resulting in the conversion of the inactive GTPase to the active form capable of transducing signals. The PH domain has multiple functions. These splice variants contain a fragment that was originally identified as Ht31 (See Carr et al 1991) which acts as a scaffolding protein to regulate the Rho signaling pathway and as protein kinase A-anchoring protein creating a coordination of these two signalling pathways. Diviani et al. found that in HEK293 cells LPA induced stimulation preferentially activates AKAP13 via G-alpha12. As yet targets for the anchored PKA have not been identified. AKAP13 and Rho do not appear to be phosphorylated by PKA. Diviani et al also found that the Lbc oncogene and protooncogene splice variant show higher activation and stress fiber localization. This appears to be a result of the presence of N terminal inhibitory sequences. A similar model of regulation has been proposed for Dbl and Vav.

Contributor:

REFERENCES: 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. J Biol Chem 1991 Aug 5;266(22):14188-92 Diviani D, Soderling J, Scott JD AKAP-Lbc anchors protein kinase A and nucleates Galpha 12-selective Rho-mediated stress fiber formation. J Biol Chem. 2001 Nov 23;276(47):44247-57