TY  - JOUR
A1  - Godbole, Amod
A1  - Lyga, Sandra
A1  - Lohse, Martin J.
A1  - Calebiro, Davide
T1  - Internalized TSH receptors en route to the TGN induce local G\(_{S}\)-protein signaling and gene transcription
JF  - Nature Communications
N2  - A new paradigm of G-protein-coupled receptor (GPCR) signaling at intracellular sites has recently emerged, but the underlying mechanisms and functional consequences are insufficiently understood. Here, we show that upon internalization in thyroid cells, endogenous TSH receptors traffic retrogradely to the trans-Golgi network (TGN) and activate endogenous Gs-proteins in the retromer-coated compartment that brings them to the TGN. Receptor internalization is associated with a late cAMP/protein kinase A (PKA) response at the Golgi/TGN. Blocking receptor internalization, inhibiting PKA II/interfering with its Golgi/TGN localization, silencing retromer or disrupting Golgi/TGN organization all impair efficient TSH-dependent cAMP response element binding protein (CREB) phosphorylation. These results suggest that retrograde trafficking to the TGN induces local G\(_{S}\)-protein activation and cAMP/PKA signaling at a critical position near the nucleus, which appears required for efficient CREB phosphorylation and gene transcription. This provides a new mechanism to explain the functional consequences of GPCR signaling at intracellular sites and reveals a critical role for the TGN in GPCR signaling.
KW  - G protein-coupled receptors
KW  - fluorescence imaging
KW  - hormone receptors
KW  - trans-Golgi network
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170375
VL  - 8
IS  - 443
ER  - 
TY  - JOUR
A1  - Weigand, Isabel
A1  - Ronchi, Cristina L.
A1  - Rizk-Rabin, Marthe
A1  - Dalmazi, Guido Di
A1  - Wild, Vanessa
A1  - Bathon, Kerstin
A1  - Rubin, Beatrice
A1  - Calebiro, Davide
A1  - Beuschlein, Felix
A1  - Bertherat, Jérôme
A1  - Fassnacht, Martin
A1  - Sbiera, Silviu
T1  - Differential expression of the protein kinase A subunits in normal adrenal glands and adrenocortical adenomas
JF  - Scientific Reports
N2  - Somatic mutations in protein kinase A catalytic α subunit (PRKACA) were found to be causative for 30-40% of cortisol-producing adenomas (CPA) of the adrenal gland, rendering PKA signalling constitutively active. In its resting state, PKA is a stable and inactive heterotetramer, consisting of two catalytic and two regulatory subunits with the latter inhibiting PKA activity. The human genome encodes three different PKA catalytic subunits and four different regulatory subunits that are preferentially expressed in different organs. In normal adrenal glands all regulatory subunits are expressed, while CPA exhibit reduced protein levels of the regulatory subunit IIβ. In this study, we linked for the first time the loss of RIIβ protein levels to the PRKACA mutation status and found the down-regulation of RIIβ to arise post-transcriptionally. We further found the PKA subunit expression pattern of different tumours is also present in the zones of the normal adrenal cortex and demonstrate that the different PKA subunits have a differential expression pattern in each zone of the normal adrenal gland, indicating potential specific roles of these subunits in the regulation of different hormones secretion.
KW  - kinases
KW  - immunohistochemistry
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-157952
VL  - 7
IS  - 49
ER  -