Molecular characterization of a cDNA that encodes six isoforms of a novel murine A kinase anchor protein

We have cloned cDNA that encodes six novel A kinase anchor proteins (collectively named AKAP-KL). AKAP-KL diversity is generated by alternative mRNA splicing and utilization of two translation initiation codons, AKAP-KL polypeptides are evident in lung, kidney, and cerebellum, but are absent from many tissues. Different isoforms predominate in different tissues, Thus, AKAP-KL expression is differentially regulated in vivo. All AKAP-KL isoforms contain a 20-residue domain that avidly binds (K-d similar to 10 nM) regulatory subunits (RII) of protein kinase All and is highly homologous with the RII tethering site in neuronal AKAP75. The distribution of AKAP-KL is strikingly asymmetric (polarized) in situ, Anchor protein accumulates near the inner, apical surface of highly polarized epithelium in tubules of nephrons, Both RII and AKAP-KL are enriched at an intracellular site that lies just below the plasma membrane of alveolar epithelial cells in lung AKAP-KL interacts with and modulates the structure of the actin cytoskeleton in transfected cells, We also demonstrate that the tethering domain of AKAP-KL avidly ligates RII subunits in intact cells. AKAP-KL may be involved in (a) establishing polarity in signaling systems and (b) physically and functionally integrating PKAII isoforms with downstream effecters to capture, amplify, and precisely focus diffuse, trans-cellular signals carried by cAMP.