PAP7, a PBR/PKA-RIalpha-associated protein: a new element in the relay of the hormonal induction of steroidogenesis.
The precise mechanism by which the hormone-induced minimal cAMP levels act at the mitochondria to activate cholesterol transport and steroid synthesis is unknown. We propose that this mechanism involves a macromolecular signaling complex where a newly identified peripheral-type benzodiazepine receptor (PBR)-associated protein (PAP7) binds the regulatory subunit RIalpha of the cAMP-dependent protein kinase A (PKA), thus allowing for local efficient catalytic activation and phosphorylation of the substrate steroidogenesis acute regulatory protein (StAR), leading to cholesterol transfer from the low affinity StAR to the high affinity PBR cholesterol binding protein. The mouse and human PAP7 proteins were cloned, their genomic organization and chromosomal localization characterized, their tissue distribution evaluated and subcellular localization defined. PAP7 is highly expressed in steroidogenic tissues, where it follows the pattern of PKA-RIalpha expression and data from a human adrenal disease suggest that it participates in PKA-RIalpha-mediated tumorigenesis and hormone-independent hypercortisolism. PAP7 is localized in the Golgi and mitochondria and inhibition of PAP7 expression results in reduced hormone-induced cholesterol transport into mitochondria and decreased steroid formation. Taken together, these data suggest that PAP7 functions as an A-kinase anchoring protein (AKAP) critical in the cAMP-dependent steroid formation.
Liu
Jun
J
Division of Hormone Research, Department of Cell Biology, Georgetown University Medical Center, 3900 Reservoir Road NW, Washington, DC 20057, USA.
Li
Hua
H
Papadopoulos
Vassilios
V
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D006728:Hormones / Q000502:physiology; D006801:Humans; D008565:Membrane Proteins; D008954:Models, Biological; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry; D011963:Receptors, GABA-A / Q000737:chemistry / Q000502:physiology*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013256:Steroids / Q000096:biosynthesis / Q000502:physiology*
C449459:ACBD3 protein, human; C486730:Acbd3 protein, mouse; D048868:Adaptor Proteins, Signal Transducing; D006728:Hormones; D008565:Membrane Proteins; D010446:Peptide Fragments; D011963:Receptors, GABA-A; D013256:Steroids; D017868:Cyclic AMP-Dependent Protein Kinases