In baker's yeast (Saccharomyces cerevisiae), Trk1, a member of the superfamily of K-transporters (SKT), is the main K+ uptake system under conditions when its concentration in the environment is low. Structurally, Trk1 is made up of four domains, each similar and homologous to a K-channel α subunit. Because most K-channels are proteins containing four channel-building α subunits, Trk1 could be functional as a monomer. However, related SKT proteins TrkH and KtrB were crystallised as dimers, and for Trk1, a tetrameric arrangement has been proposed based on molecular modelling. Here, based on Bimolecular Fluorescence Complementation experiments and single-molecule fluorescence microscopy combined with molecular modelling; we provide evidence that Trk1 can exist in the yeast plasma membrane as a monomer as well as a dimer. The association of monomers to dimers is regulated by the K+ concentration.
- MeSH
- Biological Transport MeSH
- Cell Membrane metabolism MeSH
- Potassium metabolism MeSH
- Fungal Proteins metabolism MeSH
- Cation Transport Proteins * genetics metabolism MeSH
- Saccharomyces cerevisiae Proteins * genetics metabolism MeSH
- Saccharomyces cerevisiae metabolism MeSH
- Translocation, Genetic MeSH
- Carrier Proteins metabolism MeSH
- Publication type
- Journal Article MeSH
Emerging experimental evidence suggests tau pathology spreads between neuroanatomically connected brain regions in a prion-like manner in Alzheimer's disease (AD). Tau seeding, the ability of prion-like tau to recruit and misfold naïve tau to generate new seeds, is detected early in human AD brains before the development of major tau pathology. Many antitumour drugs have been reported to confer protection against neurodegeneration, supporting the repurposing of approved and experimental or investigational oncology drugs for AD therapy. In this study, we evaluated whether antitumour drugs that abrogate the generation of seed-competent aggregates of tau Repeat 3 (R3) domain peptides can prevent tau seeding and toxicity in Tau-RD P301S FRET Biosensor cells and Caenorhabditis elegans. We demonstrate that drugs that interact with the N-terminal VQIVYK or the C-terminal region housing the Cys322 prevent R3 dimerisation, abolishing the generation of prion-like R3 seeds. Preformed R3 seeds (fibrils) capped with, or R3 seeds formed in the presence of VQIVYK- or Cys322-targeting drugs have a reduced potency to cause aggregation of naïve tau in biosensor cells and protect worms from aggregate toxicity. These findings indicate that VQIVYK- or Cys322-targeting drugs may act as prophylactic agents against tau seeding.
In contrast to the continuous increase in survival rates for many cancer entities, colorectal cancer (CRC) and pancreatic cancer are predicted to be ranked among the top 3 cancer-related deaths in the European Union by 2025. Especially, fighting metastasis still constitutes an obstacle to be overcome in CRC and pancreatic cancer. As described by Fearon and Vogelstein, the development of CRC is based on sequential mutations leading to the activation of proto-oncogenes and the inactivation of tumour suppressor genes. In pancreatic cancer, genetic alterations also attribute to tumour development and progression. Recent findings have identified new potentially important transcription factors in CRC, among those the activating transcription factor 2 (ATF2). ATF2 is a basic leucine zipper protein and is involved in physiological and developmental processes, as well as in tumorigenesis. The mutation burden of ATF2 in CRC and pancreatic cancer is rather negligible; however, previous studies in other tumours indicated that ATF2 expression level and subcellular localisation impact tumour progression and patient prognosis. In a tissue- and stimulus-dependent manner, ATF2 is activated by upstream kinases, dimerises and induces target gene expression. Dependent on its dimerisation partner, ATF2 homodimers or heterodimers bind to cAMP-response elements or activator protein 1 consensus motifs. Pioneering work has been performed in melanoma in which the dual role of ATF2 is best understood. Even though there is increasing interest in ATF2 recently, only little is known about its involvement in CRC and pancreatic cancer. In this review, we summarise the current understanding of the underestimated 'cancer gene chameleon' ATF2 in apoptosis, epithelial-to-mesenchymal transition and microRNA regulation and highlight its functions in CRC and pancreatic cancer. We further provide a novel ATF2 3D structure with key phosphorylation sites and an updated overview of all so-far available mouse models to study ATF2 in vivo.
- MeSH
- Apoptosis genetics MeSH
- Epithelial-Mesenchymal Transition genetics MeSH
- Humans MeSH
- MicroRNAs genetics MeSH
- Mutation genetics MeSH
- Neoplasms genetics pathology MeSH
- Disease Progression MeSH
- Activating Transcription Factor 2 genetics MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
- MeSH
- Allosteric Regulation * MeSH
- Cell Membrane enzymology MeSH
- Escherichia coli enzymology MeSH
- Haemophilus influenzae enzymology MeSH
- Membrane Proteins metabolism MeSH
- Providencia enzymology MeSH
- Serine Proteases metabolism MeSH
- Publication type
- Journal Article MeSH
- Comment MeSH
- Research Support, Non-U.S. Gov't MeSH
Receptory pro lidský epidermální růstový faktor (epidermal growth factor receptor; EGFR) jsou silným mediátorem pro růst buněk a jejich vývoj. Skupina receptorů má celkem 4 členy: HER1, HER2, HER3 a HER4. Receptory jsou funkční pro přenos signálu až po vzájemném spojení dvou receptorů navzájem, tzv. dimerizaci. Nejlepší přenos signálu se děje cestou heterodimeru HER2 a HER3. Zavedení trastuzumabu do léčby HER2 pozitivního karcinomu prsu změnilo prognózu této skupiny nádorů. Nejčastějším mechanismem rezistence jsou změny oblasti receptoru jako např. alterace v oblasti vazebného místa maskováním epitopu, sekrece receptoru p95HER2 a mutace oblasti tyrozinkinázové (TK) intracelulární domény receptoru. Nejčastější příčinou rezistence mimo receptor jsou signalizace cestou heterodimerů, které vznikly spojením s jinými receptory, jako např. insulin-like growth factor receptor-1 (IGF1R), nebo overexprese ligandů. Dalším možným mechanismem je ztráta kontrolních funkcí v oblasti přenosu signálu (změny oblasti PTEN) nebo aktivaci signální dráhy v dalším průběhu (cestou PI3K-Akt, MEK, MAPK – mitogen activated protein kinase).
Epidermal growth factor receptors (EGFR) are a strong mediator in cell growth and development. The receptor group has four members - HER1, HER2, HER3 and HER4. The receptors are functional for signal transmitting only after a fusion of two receptors, a so-called dimerisation. The signals transfer the best via the heterodimer of HER2 and HER3. Introducing trastuzumab into the treatment of HER2-positive breast carcinoma has led to a change in prognosis for this group of tumours. The most common resistance mechanism are changes to the receptor area, for example alterations to the binding site by masking the epitope, secretion of p95HER2 receptor and mutations of the TK intracellular domain of the receptor. The most common reasons for resistance that are extraneous to the receptor itself are signalisation via heterodimers that were created by bonding with different receptors (for example insulin-like growth factor receptor - IGF1R) or over-expression the ligands. Loss of control functions in the area of signal transmission (changes in the PTEN zone) or subsequent activation of the signal route (via PI3K-Akt, MEK, MAPK – mitogen activated protein kinase).
- Keywords
- heterodimery, PTEN, PI3K, mTOR, p95HER2,
- MeSH
- Drug Resistance, Neoplasm genetics MeSH
- Humans MeSH
- Antibodies, Monoclonal administration & dosage pharmacology MeSH
- Tumor Suppressor Proteins genetics metabolism drug effects MeSH
- Breast Neoplasms drug therapy genetics pathology MeSH
- Receptor, ErbB-2 antagonists & inhibitors MeSH
- Check Tag
- Humans MeSH
- Female MeSH
