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UniProt release 2020_05

Published October 7, 2020

Headline

PCK1 vacillating between gluconeogenesis and lipogenesis

Lipid metabolism is a tightly regulated process, which relies on sterol regulatory element-binding (SREBPs) transcription factors for the activation of genes involved in the synthesis of fatty acids, triglycerides, and cholesterol. In resting conditions, when the levels of cholesterol are sufficient, SREBPs are present as precursors in the endoplasmic reticulum (ER) membrane in complex with a protein called SCAP. SCAP also interacts with a member of the ER resident INSIG protein family. The interaction with INSIG ensures that the SCAP-SREBP complex is retained in the ER. When cholesterol levels drop, INSIG and SCAP no longer bind and the SCAP-SREBP complex is transported to the Golgi apparatus, where SREBP is cleaved and its cytosolic N-terminal transcription factor domain is freed to translocate to the nucleus and activate transcription.

There are cells, however, that do not bother about regulation and just desperately need lipogenesis to proliferate. These are cancer cells. How do they achieve the synthesis of enough lipids in normal sterol levels, in conditions in which lipogenesis would normally be inhibited? The answer came from a study in hepatocellular carcinoma (HCC) cell lines. In these cells, activation with IGF1, a stimulus critical for HCC development, leads to a cascade of phosphorylation, which starts with AKT1. Activated AKT1 in turn phosphorylates PCK1, which is then translocated from the cytosol to the ER and phosphorylates INSIG. This impairs INSIG binding to the SCAP-SREBP complex, resulting in the release of the complex from the ER to the Golgi apparatus, with subsequent SERBP activation.

The discovery of PCK1 involvement in this process comes as a surprise. PCK1 is not known to be involved in lipogenesis regulation, nor to have a kinase activity. It is a rate-limiting enzyme of gluconeogenesis, a pathway that generates glucose from certain non-carbohydrate carbon substrates. In this pathway, it converts oxaloacetate into phosphoenolpyruvate. PCK1 phosphorylation by AKT1 uncovers its cryptic kinase activity and redirects it to a completely different process. Cancer cells favor glycolysis to provide energy and metabolic intermediates, and suppress gluconeogenesis. For these cells, PCK1 diversion is necessary for cell growth, as expression of a PCK1 nonphosphorylatable mutant inhibits cell proliferation, and is costless, as inhibition of gluconeogenesis is not deleterious. Although the results have been produced in HCC cells, this process may also play a role in other cancer types. Indeed, AKT1 activation has been shown in melanoma, glioblastoma and non-small cell lung carcinoma cells.

PCK1-induced activation of SREBP1 may also occur in normal hepatocytes. In mice that were refed with glucose after 24 hours of fasting, phosphorylation of AKT1, PCK1, and INSIG proteins, as well as cleavage of SREBP1, were markedly enhanced in normal liver. These observations suggest that in vivo blood glucose levels may regulate the PCK1-mediated phosphorylation of INSIG proteins and the activation of SREBP. This might point toward a potential mechanism underlying overnutrition-promoted nonalcoholic fatty liver diseases.

As of this release, proteins involved in this new regulatory pathway have been updated and are available in UniProtKB/Swiss-Prot.

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Cross-references to CPTC

Cross-references have been added to CPTC, the CPTAC Antibody Portal. This portal serves as a National Cancer Institute (NCI) community resource that provides access to a large number of standardized renewable affinity reagents (to cancer-associated targets) and accompanying characterization data.

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DR   CPTC; P31751; 6 antibodies.

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<dbReference type="CPTC" id="P31751">
  <property type="antibodies" value="6 antibodies"/>
</dbReference>

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Example: P31751

uniprot:P31751
  rdfs:seeAlso <http://purl.uniprot.org/cptc/P31751> .
<http://purl.uniprot.org/cptc/P31751>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/CPTC> ;
  rdfs:comment "6 antibodies" .

Cross-references to BMRB

Cross-references have been added to the BMRB database, the Biological Magnetic Resonance Data Bank. BMRB collects, annotates, archives, and disseminates spectral and quantitative data derived from NMR spectroscopic investigations of biological macromolecules and metabolites.

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Cross-references have been added to the PCDDB database, the Protein Circular Dichroism Data Bank. PCDDB is a public repository that archives and freely distributes circular dichroism (CD) and synchrotron radiation CD spectral data and their associated experimental metadata.

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Changes to the controlled vocabulary of human diseases

New diseases:

Modified diseases:

Deleted diseases

  • Arthrogryposis, distal, 8
  • Ectodermal dysplasia, anhidrotic, with immunodeficiency, osteopetrosis and lymphedema
  • Immunodeficiency, NEMO-related, without anhidrotic ectodermal dysplasia
  • Recurrent isolated invasive pneumococcal disease 1
  • Recurrent isolated invasive pneumococcal disease 2

Changes to the controlled vocabulary for PTMs

New terms for the feature key 'Glycosylation' ('CARBOHYD' in the flat file):

  • O-alpha-linked (GlcNAc) threonine
  • O-linked (Glc) threonine

Changes to keywords

New keyword:

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