A-kinase anchor protein 75 increases the rate and magnitude of cAMP signaling to the nucleus

Antonio Feliciello, Ying Li, Enrico V. Awedimento, Max E. Gottesman, Charles S. Rubin

Research output: Contribution to journalArticle

58 Scopus citations

Abstract

A-kinase anchor protein 75 (AKAP75) binds regulatory subunits (RIIα and RIIβ) of type II protein kinase A (PKAII) isoforms and targets the resulting complexes to sites in the cytoskeleton that abut the plasma membrane [1-7]. Co-localization of AKAP75-PKAII with adenylate cyclase and PKA substrate/effector proteins. In cytoskeleton and plasma membrane effects a physical and functional integration of up-stream and downstream signaling proteins, thereby ensuring efficient propagation of signals carried by locally generated cyclic AMP (cAMP) [4-9]. An important, but previously untested, prediction of the AKAP model is that efficient, cyclic nucleotide-dependent liberation of diffusible PKA catalytic subunits from cytoskeletonbound AKAP75-PKAII complexes will also enhance signaling to distal organelles, such as the nucleus. We tested this idea by using HEK-A75 cells, in which PKAII isoforms are immobilized in cortical cytoskeleton by AKAP75. Abilities of HEK-A75 and control calls (with cytoplasmically dispersed PKAII isoforms) to respond to increases in cAMP content were compared. Cells with anchored PKAII exhibited a threefold higher level of nuclear catalytic subunit content and 4-10-fold greater increments in phosphorylation of a regulatory serine residue in cAMP response element binding protein (CREB) and in phosphoCREB-stimulated transcription of the c-fos gene. Each effect occurred more rapidly in cells containing targeted AKAP75-PKAII complexes. Thus, anchoring of PKAII in actin cortical cytoskeleton increases the rate, magnitude and sensitivity of cAMP signaling to the nucleus.

Original languageEnglish (US)
Pages (from-to)1011-1014
Number of pages4
JournalCurrent Biology
Volume7
Issue number12
DOIs
StatePublished - Dec 1 1997

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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    Feliciello, A., Li, Y., Awedimento, E. V., Gottesman, M. E., & Rubin, C. S. (1997). A-kinase anchor protein 75 increases the rate and magnitude of cAMP signaling to the nucleus. Current Biology, 7(12), 1011-1014. https://doi.org/10.1016/S0960-9822(06)00424-6