Interaction of AIP with protein kinase A (cAMP-dependent protein kinase). 2018

Marie Helene Schernthaner-Reiter, and Giampaolo Trivellin, and Constantine A Stratakis
Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene cause mostly somatotropinomas and/or prolactinomas in a subset of familial isolated pituitary adenomas (FIPA). AIP has been shown to interact with phosphodiesterases (PDEs) and G proteins, suggesting a link to the cyclic AMP (cAMP)-dependent protein kinase (PKA) pathway. Upregulation of PKA is seen in sporadic somatotropinomas that carry GNAS mutations, and those in Carney complex that are due to PRKAR1A mutations. To elucidate the mechanism of AIP-dependent pituitary tumorigenesis, we studied potential functional and physical interactions of AIP with PKA's main subunits PRKAR1A (R1α) and PRKACA (Cα). We found that AIP physically interacts with both R1α and Cα; this interaction is enhanced when all three components are present, but maintained during Cα-R1α dissociation by PKA activation, indicating that AIP binds Cα/R1α both in complex and separately. The interaction between AIP and R1α/Cα is reduced when the frequent AIP pathogenic mutation p.R304* is present. AIP protein levels are regulated both by translation and the ubiquitin/proteasome pathway and Cα stabilizes both AIP and R1α protein levels. AIP reduction by siRNA leads to an increase of PKA activity, which is disproportionately enhanced during PDE4-inhibition. We show that AIP interacts with the PKA pathway on multiple levels, including a physical interaction with both the main regulatory (R1α) and catalytic (Cα) PKA subunits and a functional interaction with PDE4-dependent PKA activation. These findings provide novel insights on the mechanisms of AIP-dependent pituitary tumorigenesis.

UI MeSH Term Description Entries
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D045744 Cell Line, Tumor A cell line derived from cultured tumor cells. Tumor Cell Line,Cell Lines, Tumor,Line, Tumor Cell,Lines, Tumor Cell,Tumor Cell Lines
D047908 Intracellular Signaling Peptides and Proteins Proteins and peptides that are involved in SIGNAL TRANSDUCTION within the cell. Included here are peptides and proteins that regulate the activity of TRANSCRIPTION FACTORS and cellular processes in response to signals from CELL SURFACE RECEPTORS. Intracellular signaling peptide and proteins may be part of an enzymatic signaling cascade or act through binding to and modifying the action of other signaling factors. Intracellular Signaling Peptides,Intracellular Signaling Proteins,Peptides, Intracellular Signaling,Proteins, Intracellular Signaling,Signaling Peptides, Intracellular,Signaling Proteins, Intracellular
D049912 Growth Hormone-Secreting Pituitary Adenoma A pituitary tumor that secretes GROWTH HORMONE. In humans, excess HUMAN GROWTH HORMONE leads to ACROMEGALY. Pituitary Adenoma, GH-Secreting,Pituitary Growth Hormone-Secreting Adenoma,Somatotroph Adenoma,Acromegaly Due To Pituitary Adenoma,GH-Secreting Pituitary Adenoma,Isolated Familial Somatotropinoma,Pituitary Adenoma, Growth Hormone-Secreting,Somatotrophinoma, Familial,Somatotropinoma, Familial Isolated,Adenoma, Somatotroph,Adenomas, Somatotroph,GH Secreting Pituitary Adenoma,GH-Secreting Pituitary Adenomas,Pituitary Adenoma, GH Secreting,Pituitary Adenoma, Growth Hormone Secreting,Pituitary Adenomas, GH-Secreting,Pituitary Growth Hormone Secreting Adenoma,Somatotroph Adenomas
D051381 Rats The common name for the genus Rattus. Rattus,Rats, Laboratory,Rats, Norway,Rattus norvegicus,Laboratory Rat,Laboratory Rats,Norway Rat,Norway Rats,Rat,Rat, Laboratory,Rat, Norway,norvegicus, Rattus
D054751 Cyclic AMP-Dependent Protein Kinase Catalytic Subunits Specific enzyme subunits that form the active sites of the type I and type II cyclic-AMP protein kinases. Each molecule of enzyme contains two catalytic subunits. Cyclic AMP-Dependent Protein Kinase Catalytic Subunit,Protein Kinase A, Catalytic Subunits,cAMP-Dependent Protein Kinase, alpha-Catalytic Subunit,cAMP-Dependent Protein Kinase, beta-Catalytic Subunit,cAMP-Dependent Protein Kinase, gamma-Catalytic Subunit,Cyclic AMP Dependent Protein Kinase Catalytic Subunit,Cyclic AMP Dependent Protein Kinase Catalytic Subunits,cAMP Dependent Protein Kinase, alpha Catalytic Subunit,cAMP Dependent Protein Kinase, beta Catalytic Subunit,cAMP Dependent Protein Kinase, gamma Catalytic Subunit
D054756 Cyclic AMP-Dependent Protein Kinase RIalpha Subunit A type I cAMP-dependent protein kinase regulatory subunit that plays a role in confering CYCLIC AMP activation of protein kinase activity. It has a lower affinity for cAMP than the CYCLIC-AMP-DEPENDENT PROTEIN KINASE RIBETA SUBUNIT. Protein Kinase A, RIalpha Subunit,Cyclic-AMP-Dependent Protein Kinase RIalpha Subunit,RI alpha, cAMP Protein Kinase,RIalpha, PKA,RIalpha, Protein Kinase A,RIalpha, cAMP Protein Kinase,Regulatory Subunit RIalpha, Cyclic-AMP-Dependent Protein Kinase,Cyclic AMP Dependent Protein Kinase RIalpha Subunit,PKA RIalpha,Regulatory Subunit RIalpha, Cyclic AMP Dependent Protein Kinase
D055550 Protein Stability The ability of a protein to retain its structural conformation or its activity when subjected to physical or chemical manipulations. Protein Stabilities,Stabilities, Protein,Stability, Protein
D058988 Phosphodiesterase 4 Inhibitors Compounds that specifically inhibit PHOSPHODIESTERASE 4. PDE-4 Inhibitor,PDE4 Inhibitor,Phosphodiesterase 4 Inhibitor,Phosphodiesterase Type 4 Inhibitor,PDE-4 Inhibitors,PDE4 Inhibitors,Phosphodiesterase Type 4 Inhibitors,4 Inhibitor, Phosphodiesterase,Inhibitor, PDE-4,Inhibitor, PDE4,Inhibitor, Phosphodiesterase 4,Inhibitors, PDE-4,Inhibitors, PDE4,Inhibitors, Phosphodiesterase 4,PDE 4 Inhibitor,PDE 4 Inhibitors

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