Membrane-bound cAMP-dependent protein kinase controls cAMP-induced differentiation in PC12 cells.

The A126 cell line, a derivative of PC12, is defective in cAMP-induced transcription and does not differentiate in the presence of cAMP. In these cells overexpression of a cAMP-dependent protein kinase (PKA) anchor protein, AKAP75, and of the PKA catalytic subunit substantially increased the fraction of PKAII bound to the membrane, stimulated the transcription of cAMP-induced genes, and induced terminal differentiation. Conversely, wild type PC12 cells expressing a derivative of the AKAP75 protein, AKAP45, which binds the PKA regulatory subunits RII, but fails to locate them to the membranes, induced translocation of PKAII to the cytosol.

Membrane localization of cAMP-dependent protein kinase amplifies cAMP signaling to the nucleus in PC12 cells.

The A126 cell line, in contrast to its PC12 parent, does not differentiate, accumulate nuclear cAMP-dependent protein kinase A (PKA) catalytic subunit, or transcribe cAMP-dependent promoters in response to cAMP. Total PKA is reduced by 50% and is partly resistant to cAMP-induced dissociation in vivo. Unlike PC12, where PKAII is membrane-associated, PKAII is exclusively cytosolic in A126.

Ki-ras oncogene interferes with the expression of cyclic AMP-dependent promoters.

The expression of thyroglobulin and other thyroid-specific markers depends upon the activation of protein kinase A (PKA) by cyclic AMP. A rat thyroid cell line dedifferentiates when transformed with Ki-ras oncogene. The decrease in thyroglobulin gene expression parallels a reduction in the level of PKA nuclear catalytic subunit.