Human Molecular Genetics Advance Access published online on September 8, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl239
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1 Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bldg. 18T, Room 101, 18 Library Drive, Bethesda, MD 20892, USA
* To whom correspondence should be addressed. The human PRKAR1A gene encodes the regulatory subunit 1-alpha (RI
Received July 13, 2006
Revised August 24, 2006
Accepted August 24, 2006
Article
Depletion of type IA regulatory subunit (RI
Manos Mavrakis 1 *, Jennifer Lippincott-Schwartz 2, Constantine A. Stratakis 3, and Ioannis Bossis 3
) of protein kinase A (PKA) in mammalian cells and tissues activates mTOR and causes autophagic deficiency
2 Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bldg. 18T, 18 Library Drive, Bethesda, MD 20892, USA
3 Section on Endocrinology and Genetics, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bldg. 10, CRC, 10 Center Drive Bethesda, MD 20892, USA
Manos Mavrakis, E-mail: mavrakim{at}mail.nih.gov
Abstract 
) of the cAMP-dependent protein kinase (PKA) holoenzyme. Regulation of the catalytic activity of PKA is the only well studied function of RI. Inactivating PRKAR1A mutations cause primary pigmented nodular adrenocortical disease (PPNAD) or Carney Complex (CNC), an inherited syndrome associated with abnormal skin pigmentation and multiple neoplasias, including PPNAD. Histochemistry of tissues from CNC patients is indicative of autophagic deficiency and this led us to investigate the relationship between RI and mammalian autophagy. We found that fluorescently-tagged RI associates with late endosomes and autophagosomes in cultured cells. The number of autophagosomes in prkar1a-/- mouse embryonic fibroblasts (MEFs) was reduced compared to wild-type MEFs. RI co-immunoprecipitated with mTOR kinase, a major regulator of autophagy. Phosphorylated mTOR levels and mTOR activity were dramatically increased in prkar1a-/- mouse cells and in HEK 293 cells with RI levels reduced by siRNA. Finally, phosphorylated-mTOR and mTOR activity were increased in CNC cells and in PPNAD tissues. These data suggest that RI deficiency decreases autophagy by activation of mTOR, providing a molecular basis to autophagic deficiency in PPNAD.
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