A-KINASE ANCHOR PROTEIN-75 INCREASES THE RATE AND MAGNITUDE OF CAMP SIGNALING TO THE NUCLEUS

A-kinase anchor protein 75 (AKAP75) binds regulatory subunits (RII alp ha and RII beta) of type II protein kinase A (PKAII) isoforms and targ ets the resulting complexes to sites in the cytoskeleton that abut the plasma membrane [1-7], Go-localization of AKAP75-PKAII with adenylate cyclase and PKA substrate/effector proteins in cytoskeleton and plasm a membrane effects a physical and functional integration of up-stream and downstream signaling proteins, thereby ensuring efficient propagat ion of signals carried by locally generated cyclic AMP (cAMP) [4-9], A n important, but previously untested, prediction of the AKAP model is that efficient, cyclic nucleotide-dependent liberation of diffusible P KA catalytic subunits from cytoskeleton-bound AKAP75-PKAII complexes w ill also enhance signaling to distal organelles, such as the nucleus, We tested this idea by using HEK-A75 cells, in which PKAII isoforms ar e immobilized in cortical cytoskeleton by AKAP75, Abilities of HEK-A75 and control cells (with cytoplasmically dispersed PKAII isoforms) to respond to increases in cAMP content were compared, Cells with anchore d PKAII exhibited a threefold higher level of nuclear catalytic subuni t content and 4-10-fold greater increments in phosphorylation of a reg ulatory serine residue in cAMP response element binding protein (CREB) and in phosphoCREB-stimulated transcription of the c-fos gene, Each e ffect occurred more rapidly in cells containing targeted AKAP75-PKAII complexes, Thus, anchoring of PKAII in actin cortical cytoskeleton inc reases the rate, magnitude and sensitivity of cAMP signaling to the nu cleus.