The embryonic enzyme pyruvate kinase M2 (PKM2) has a well-established role in metabolism and is highly expressed in human cancers. Now, a team led by researchers at the University of Texas MD Anderson Cancer Center reports online on November 6, 2011 in the journal Nature that PKM2 has important non-metabolic functions in cancer formation. "Our research shows that although PKM2 plays an important role in cancer metabolism, this enzyme also has an unexpected pivotal function – it regulates cell proliferation directly," said senior author Dr. Zhimin Lu, associate professor in the Department of Neuro-Oncology at MD Anderson. "Basically, PKM2 contributes directly to gene transcription for cell growth – a finding that was very surprising." The researchers demonstrated that PKM2 is essential for epidermal growth factor receptor (EGFR)–promoted beta-catenin activation, which leads to gene expression, cell growth, and tumor formation. They also discovered that levels of beta-catenin phosphorylation and PKM2 in the cell nucleus are correlated with brain tumor malignancy and prognosis and might serve as biomarkers for customized treatment with Src inhibitors. In response to epidermal growth factor (EGF), the team found, PKM2 moves into the cell nucleus and binds to beta-catenin that has had a phosphate atom and three oxygen atoms attached at a specific spot called Y333 by the protein c-Src. This binding is essential for beta-catenin activation and expression of downstream gene cyclin D1. This newly discovered way to regulate beta-catenin is independent of the Wnt signaling pathway previously known to activate beta-catenin. In metabolism, PKM2 enhances oxygen-driven processing of sugar known as aerobic glycolysis or the Warburg effect found in tumor cells.
Researchers at the RIKEN Brain Science Institute (BSI) in Japan have discovered a key mechanism responsible for selectively degrading aggregates of ubiquitinated proteins from the cell. Their findings indicate that the capture and removal of such aggregates is mediated by the phosphorylation of a protein called p62, opening the door to new avenues for treating neurodegenerative diseases such as Huntington's disease and Alzheimer's disease. One of the most important activities of a cell is the production of proteins, which play essential functions in everything from oxygen transport, to immune defense, to food digestion. Equally important to the cell's survival is how it deals with these proteins when they pass their expiration date: damaged or misfolded proteins have been associated with a range of debilitating conditions, including neurodegenerative diseases such as Alzheimer's disease. In eukaryotic cells, the recycling of damaged or misformed proteins is governed by a small regulatory protein called ubiquitin in a process called "ubiquitination." By attaching itself to a protein, a ubiquitin molecule can tag the protein for destruction by proteasomes, large protein complexes that degrade and recycle unneeded proteins in the cell. This recycling of proteins by proteasomes is crucial to the maintenance of cellular homeostasis. With their research, the BSI research group sought to shed light on one area where proteasome-based recycling falls short: protein complexes or aggregates, which proteasomes have trouble degrading. The group shows that this weakness is made up for by the phosphorylation of a protein called p62 at the serine 403 (S403) loci of its ubiquitin-associated (UBA) domain, which triggers a catabolic process called selective autophagy that degrades protein aggregates.