PMID- 29726992
OWN - NLM
STAT- MEDLINE
DCOM- 20191203
LR  - 20210109
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 27
IP  - 15
DP  - 2018 Aug 1
TI  - Interaction of AIP with protein kinase A (cAMP-dependent protein kinase).
PG  - 2604-2613
LID - 10.1093/hmg/ddy166 [doi]
AB  - 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 (R1alpha) and PRKACA (Calpha). We 
      found that AIP physically interacts with both R1alpha and Calpha; this interaction is 
      enhanced when all three components are present, but maintained during Calpha-R1alpha 
      dissociation by PKA activation, indicating that AIP binds Calpha/R1alpha both in complex 
      and separately. The interaction between AIP and R1alpha/Calpha 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 Calpha 
      stabilizes both AIP and R1alpha 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 (R1alpha) and 
      catalytic (Calpha) PKA subunits and a functional interaction with PDE4-dependent PKA 
      activation. These findings provide novel insights on the mechanisms of 
      AIP-dependent pituitary tumorigenesis.
CI  - Published by Oxford University Press 2018. This work is written by US Government 
      employees and is in the public domain in the US.
FAU - Schernthaner-Reiter, Marie Helene
AU  - Schernthaner-Reiter MH
AD  - Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute 
      of Child Health and Human Development, National Institutes of Health, Bethesda, 
      MD, USA.
FAU - Trivellin, Giampaolo
AU  - Trivellin G
AD  - Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute 
      of Child Health and Human Development, National Institutes of Health, Bethesda, 
      MD, USA.
FAU - Stratakis, Constantine A
AU  - Stratakis CA
AD  - Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute 
      of Child Health and Human Development, National Institutes of Health, Bethesda, 
      MD, USA.
LA  - eng
GR  - J 3482/FWF_/Austrian Science Fund FWF/Austria
GR  - ZIA HD008920/HD/NICHD NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (Cyclic AMP-Dependent Protein Kinase RIalpha Subunit)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (PRKAR1A protein, human)
RN  - 0 (Phosphodiesterase 4 Inhibitors)
RN  - 0 (aryl hydrocarbon receptor-interacting protein)
RN  - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinase Catalytic Subunits)
RN  - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
RN  - EC 2.7.11.11 (PRKACA protein, human)
RN  - K676NL63N7 (Rolipram)
SB  - IM
MH  - Animals
MH  - Cell Line, Tumor
MH  - Cyclic AMP-Dependent Protein Kinase Catalytic Subunits/genetics/*metabolism
MH  - Cyclic AMP-Dependent Protein Kinase RIalpha Subunit/genetics/*metabolism
MH  - Cyclic AMP-Dependent Protein Kinases/metabolism
MH  - Growth Hormone-Secreting Pituitary Adenoma/genetics
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins/genetics/metabolism
MH  - Phosphodiesterase 4 Inhibitors/pharmacology
MH  - Protein Stability
MH  - Rats
MH  - Rolipram/pharmacology
PMC - PMC6048987
EDAT- 2018/05/05 06:00
MHDA- 2019/12/04 06:00
PMCR- 2018/05/02
CRDT- 2018/05/05 06:00
PHST- 2018/03/07 00:00 [received]
PHST- 2018/04/29 00:00 [revised]
PHST- 2018/05/01 00:00 [accepted]
PHST- 2018/05/05 06:00 [pubmed]
PHST- 2019/12/04 06:00 [medline]
PHST- 2018/05/05 06:00 [entrez]
PHST- 2018/05/02 00:00 [pmc-release]
AID - 4991971 [pii]
AID - ddy166 [pii]
AID - 10.1093/hmg/ddy166 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2018 Aug 1;27(15):2604-2613. doi: 10.1093/hmg/ddy166.