@article{Barbosa:2017:10.1091/mbc.E17-01-0075,
author = {Barbosa, S and Carreira, S and O'Hare, P},
doi = {10.1091/mbc.E17-01-0075},
journal = {MOLECULAR BIOLOGY OF THE CELL},
pages = {1565--1579},
title = {GSK-3-mediated phosphorylation couples ER-Golgi transport and nuclear stabilization of the CREB-H transcription factor to mediate apolipoprotein secretion},
url = {http://dx.doi.org/10.1091/mbc.E17-01-0075},
volume = {28},
year = {2017}
}

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TY  - JOUR
AB  - CREB-H, an ER-anchored transcription factor, plays a key role in regulating secretion in metabolic pathways, particularly triglyceride homeostasis. It controls the production both of secretory pathway components and cargoes, including apolipoproteins ApoA-IV and ApoC-II, contributing to VLDL/HDL distribution and lipolysis. The key mechanism controlling CREB-H activity involves its ER retention and forward transport to the Golgi, where it is cleaved by Golgi-resident proteases, releasing the N-terminal product, which traffics to the nucleus to effect transcriptional responses. Here we show that a serine-rich motif termed the P-motif, located in the N-terminus between serines 73 and 90, controls release of the precursor transmembrane form from the ER and its forward transport to the Golgi. This motif is subject to GSK-3 phosphorylation, promoting ER retention, while mutation of target serines and drug inhibition of GSK-3 activity coordinately induce both forward transport of the precursor and cleavage, resulting in nuclear import. We previously showed that for the nuclear product, the P-motif is subject to multiple phosphorylations, which regulate stability by targeting the protein to the SCFFbw1a E3 ubiquitin ligase. Thus phosphorylation at the P-motif provides integrated control of CREB-H function, coupling intercompartmental transport in the cytoplasm with stabilization of the active form in the nucleus.
AU  - Barbosa,S
AU  - Carreira,S
AU  - O'Hare,P
DO  - 10.1091/mbc.E17-01-0075
EP  - 1579
PY  - 2017///
SN  - 1059-1524
SP  - 1565
TI  - GSK-3-mediated phosphorylation couples ER-Golgi transport and nuclear stabilization of the CREB-H transcription factor to mediate apolipoprotein secretion
T2  - MOLECULAR BIOLOGY OF THE CELL
UR  - http://dx.doi.org/10.1091/mbc.E17-01-0075
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000402330400016&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - http://hdl.handle.net/10044/1/49444
VL  - 28
ER  - 

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