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Protein kinase A (PKA) interferes with the processing and activity of sterol regulatory element binding proteins (SREBPs)
Author(s) -
Esquejo Ryan Magadan,
Phelan Peter E.,
RoquetaRivera Manuel,
Osborne Timothy F.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.585.4
Subject(s) - sterol regulatory element binding protein , protein kinase a , microbiology and biotechnology , golgi apparatus , endoplasmic reticulum , transcription factor , phosphorylation , biology , biochemistry , kinase , brefeldin a , chemistry , gene
Several kinases are known to modulate the activity of the sterol regulatory element binding proteins (SREBPs), which are transcription factors that activate lipid biosynthesis. The inactive SREBP precursor forms are bound to the endoplasmic reticulum (ER) and require the SREBP cleavage activating protein (SCAP) to shuttle SREBPs to the Golgi, where proteases cleave and release the active SREBPs, which can then enter the nucleus and activate transcription. SREBPs are known to be down‐regulated by conditions where PKA activity is higher such as by glucagon action in the liver; however, a mechanism to explain this effect is lacking. Here, we show that PKA can block processing of SREBPs in various cells types. We used forskolin to induce PKA activity and found lower levels of mature SREBP‐1 in BCR‐ABL transformed bone marrow. We also used H‐89, a PKA inhibitor, and found higher levels of mature SREBPs in the BCR‐ABL transformed bone marrow, HeLa cells, and mouse primary hepatocytes. Preliminary results showed that H‐89 injection into mice can blunt the negative effect of glucagon on mature SREBP accumulation in the liver. In preliminary studies, we found higher amounts of SCAP in the Golgi when H‐89 is added to Chinese hamster ovary (CHO) cells that stably express GFP‐SCAP. There is a conserved putative PKA phosphorylation motif in SCAP and many phosphoproteomic studies show the site is phosphorylated in many different settings. Thus, our recent discovery points to a novel role for PKA in SREBP trafficking and activation, possibly via direct PKA phosphorylation of SCAP.