The gastrointestinal tract serves as a fast-renewing model for unraveling the multifaceted molecular mechanisms underlying remarkably rapid cell renewal, which is exclusively fueled by a small number of long-lived stem cells and their progeny. Stem cell activity is the best-characterized aspect of mucosal homeostasis in mitotically active tissues, and the dysregulation of regenerative capacity is a hallmark of epithelial immune defects. This dysregulation is frequently associated with pathologies ranging from chronic enteritis to malignancies in humans. Read More
Background: Meningiomas are the most common primary intracranial tumors in adults. While a majority of meningiomas are slow growing neoplasms that may cured by surgical resection, a subset demonstrates more aggressive behavior and insidiously recurs despite surgery and radiation, without effective alternative treatment options. Elucidation of critical mitogenic pathways in meningioma oncogenesis may offer new therapeutic strategies. Read More
Background: Antimicrobial peptides are important components of the host defence with a broad range of functions including direct antimicrobial activity and modulation of inflammation. Lack of cathelin-related antimicrobial peptide (CRAMP) was associated with higher mortality and bacterial burden and impaired neutrophil granulocyte infiltration in a model of pneumococcal meningitis. The present study was designed to characterize the effects of CRAMP deficiency on glial response and phagocytosis after exposure to bacterial stimuli. Read More
Background: Magnesium (Mg(2+)) is an essential cation implicated in carcinogenesis, solid tumor progression and metastatic potential. The Transient Receptor Potential Melastatin Member 7 (TRPM7) is a divalent ion channel involved in cellular and systemic Mg(2+) homeostasis. Abnormal expression of TRPM7 is found in numerous cancers, including colon, implicating TRPM7 in this process. Read More
Background: C-terminal Src kinase (Csk) and Csk-homologous kinase (Chk) are the major endogenous inhibitors of Src-family kinases (SFKs). They employ two mechanisms to inhibit SFKs. First, they phosphorylate the C-terminal tail tyrosine which stabilizes SFKs in a closed inactive conformation by engaging the SH2 domain in cis. Read More
Background: Phosphoinositide 3-kinase γ (PI3Kγ) and PI3Kδ are second messenger-generating enzymes with key roles in proliferation, differentiation, survival, and function of leukocytes. Deficiency of the catalytic subunits p110γ and p110δ of PI3Kγ and PI3Kδ in p110γ/δ(-/-) mice leads to defective B- and T-cell homeostasis. Here we examined the role of p110γ and p110δ in the homeostasis of neutrophils by analyzing p110γ(-/-), p110δ(-/-) and p110γ/δ(-/-) mice. Read More
Cell Commun Signal 2017 Jul 14;15(1):27. Epub 2017 Jul 14.
Division of Biomedical Sciences, Mercer University School of Medicine, Macon, Georgia.
Viruses exploit various cellular processes for their own benefit, including counteracting anti-viral responses and regulating viral replication and propagation. In the past 20 years, protein sumoylation has emerged as an important post-translational modification that is manipulated by viruses to modulate anti-viral responses, viral replication, and viral pathogenesis. The process of sumoylation is a multi-step cascade where a small ubiquitin-like modifier (SUMO) is covalently attached to a conserved ΨKxD/E motif within a target protein, altering the function of the modified protein. Read More
Background: Estrogen receptors (ER) α and β are found in both women and men in many tissues, where they have different functions, including having roles in cell proliferation and differentiation of the reproductive tract. In addition to estradiol (E2), a natural hormone, numerous compounds are able to bind ERs and modulate their activities. Among these compounds, phytoestrogens such as isoflavones, which are found in plants, are promising therapeutics for several pathologies. Read More
Cell Commun Signal 2017 Jun 29;15(1):25. Epub 2017 Jun 29.
Department of Biochemistry, BK21 PLUS Program for Creative Veterinary Science Research and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, South Korea.
Background: Hematopoietic stem cell (HSC) maintenance requires a specific microenvironment. HSC niches can be activated by tissue damaging chemotherapeutic drugs and various cell signaling molecules such as SDF-1 and FGF, which might also result in bone marrow stress. Recent research has insufficiently shown that endosteal osteolineage cells and other niche constituents recover after marrow injury. Read More
Cell Commun Signal 2017 Jun 21;15(1):24. Epub 2017 Jun 21.
Department of Biology, McMaster University, Hamilton, L8S 4K1, ON, Canada.
Background: In mammalian intestines, Notch signaling plays a critical role in mediating cell fate decisions; it promotes the absorptive (or enterocyte) cell fate, while concomitantly inhibiting the secretory cell fate (i.e. goblet, Paneth and enteroendocrine cells). Read More
The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway plays critical roles in orchestrating of immune system, especially cytokine receptors and they can modulate the polarization of T helper cells. This pathway is regulated by an array of regulator proteins, including Suppressors of Cytokine Signaling (SOCS), Protein Inhibitors of Activated STATs (PIAS) and Protein Tyrosine Phosphatases (PTPs) determining the initiation, duration and termination of the signaling cascades. Dysregulation of the JAK-STAT pathway in T helper cells may result in various immune disorders. Read More
Background: The pathogenesis of human basal-like breast cancer (BLBC) is not well understood and patients with BLBC have a poor prognosis. Expression of the epidermal growth factor receptor (EGFR) and nuclear factor-κB (NF-κB) is well-known to be upregulated in BLBC. The forkhead box C1 (FOXC1) transcription factor, an important prognostic biomarker specific for BLBC, has been shown to be induced by EGF and is critical for EGF effects in breast cancer cells. Read More
This article focusses on the role of TGF-β and its signaling crosstalk with the RHO family GTPases RAC1 and RAC1b in the progression of breast and pancreatic carcinoma. The aggressive nature of these tumor types is mainly due to metastatic dissemination. Metastasis is facilitated by desmoplasia, a peculiar tumor microenvironment and the ability of the tumor cells to undergo epithelial-mesenchymal transition (EMT) and to adopt a motile and invasive phenotype. Read More
Background: Death receptor (DR5), a well-characterized death domain-containing cell surface pro-apoptotic protein, has been suggested to suppress cancer cell invasion and metastasis. However, the underlying mechanisms have not been fully elucidated. Our recent work demonstrates that DR5 suppression promotes cancer cell invasion and metastasis through caspase-8/TRAF2-mediated activation of ERK and JNK signaling and MMP1 elevation. Read More
Background: There is compelling evidence associating senescent cells with the malignant progression of tumours. Of all senescence-related mechanisms, the so-called senescence-associated secretory phenotype (SASP) has attracted much attention. Since the pro-inflammatory cytokines IL-6 and IL-8 are consistently present in the SASP, and secreted by highly aggressive breast cancer cell lines, we aimed at elucidating their role on the less aggressive breast cancer cell line MCF-7, which does not secret these cytokines. Read More
Background: Renal cell carcinomas (RCCs) display broad resistance against conventional radio- and chemotherapies, which is due at least in part to impairments in both extrinsic and intrinsic apoptotic pathways. One important anti-apoptotic factor that is strongly overexpressed in RCCs and known to inhibit both apoptotic pathways is ARC (apoptosis repressor with a CARD domain).
Methods: Expression and subcellular distribution of ARC in RCC tissue samples and RCC cell lines were determined by immunohistochemistry and fluorescent immunohistochemistry, respectively. Read More
Infections with the human pathogen Helicobacter pylori (H. pylori) are closely associated with the development of inflammatory disorders and neoplastic transformation of the gastric epithelium. Drastic changes in the micromilieu involve a complex network of H. Read More
Background: Colorectal cancers (CRCs) that lack DNA mismatch repair function exhibit the microsatellite unstable (MSI) phenotype and are characterized by the accumulation of frameshift mutations at short repetitive DNA sequences (microsatellites). These tumors recurrently show inactivating frameshift mutations in the tumor suppressor Transforming Growth Factor Beta Receptor Type 2 (TGFBR2) thereby abrogating downstream signaling. How altered TGFBR2 signaling affects exosome-mediated communication between MSI tumor cells and their environment has not been resolved. Read More
Cell Commun Signal 2017 Mar 31;15(1):13. Epub 2017 Mar 31.
3rd Medical Department with Hematology and Medical Oncology, Hemostaseology, Rheumatology and Infectious Diseases, Laboratory for Immunological and Molecular Cancer Research, Oncologic Center, Paracelsus Medical University Salzburg, Müllner Hauptstraße 48, A-5020, Salzburg, Austria.
Hypomethylating agents (HMAs) have been widely used over the last decade, approved for use in myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML). The proposed central mechanism of action of HMAs, is the reversal of aberrant methylation in tumor cells, thus reactivating CpG-island promoters and leading to (re)expression of tumor suppressor genes. Recent investigations into the mode of action of azacitidine (AZA) and decitabine (DAC) have revealed new molecular mechanisms that impinge on tumor immunity via induction of an interferon response, through activation of endogenous retroviral elements (ERVs) that are normally epigenetically silenced. Read More
Background: Cancer represents heterogeneous and aberrantly proliferative manifestations composed of (epi)genetically and phenotypically distinct cells with a common clonal origin. Cancer stem cells (CSC) make up a rare subpopulation with the remarkable capacity to initiate, propagate and spread a malignant disease. Furthermore, CSC show increased therapy resistance, thereby contributing to disease relapse. Read More
C-Met is a receptor tyrosine kinase with multiple functions throughout embryonic development, organogenesis and wound healing and is expressed in various epithelia. The ligand of c-Met is Hepatocyte Growth Factor (HGF) which is secreted among others by mesenchymal stroma/stem (MSC) cells.Physiological c-Met functions are centred around processes that underly cellular motility and invasive growth. Read More
Background: Translationally controlled tumour protein TCTP is an anti-apoptotic protein frequently overexpressed in cancers, where high levels are often associated with poor patient outcome. TCTP may be involved in protecting cancer cells against the cytotoxic action of anti-cancer drugs. Here we study the early increase of TCTP levels in human colorectal cancer (CRC) and the regulation of TCTP expression in HCT116 colon cancer cells, in response to treatment with the anti-cancer drugs 5-FU and oxaliplatin. Read More
Treatment of acute myeloid leukemia (AML), an aggressive and heterogeneous hematological malignancy, remains a challenge. Despite advances in our understanding of the complex genetics and biology of AML pathophysiology, these findings have been translated to the clinic with only limited success, and poor outcomes persist for the majority of patients. Thus, novel treatment strategies are clearly needed for achieving deeper and prolonged remissions and for avoiding the development of resistance. Read More
Inhibitors of DNA binding and cell differentiation (Id) proteins are members of the large family of the helix-loop-helix (HLH) transcription factors, but they lack any DNA-binding motif. During development, the Id proteins play a key role in the regulation of cell-cycle progression and cell differentiation by modulating different cell-cycle regulators both by direct and indirect mechanisms. Several Id-protein interacting partners have been identified thus far, which belong to structurally and functionally unrelated families, including, among others, the class I and II bHLH transcription factors, the retinoblastoma protein and related pocket proteins, the paired-box transcription factors, and the S5a subunit of the 26 S proteasome. Read More
Background: The mammalian target of rapamycin (mTOR) is a regulator of cell proliferation, cell growth and apoptosis working through two distinct complexes: mTORC1 and mTORC2. Although much is known about the activation and inactivation of mTORC1, the processes controlling mTORC2 remain poorly characterized. Experimental and modeling studies have attempted to explain the regulation of mTORC2 but have yielded several conflicting hypotheses. Read More
Cell Commun Signal 2017 Jan 19;15(1). Epub 2017 Jan 19.
Third Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Disease and Rheumatology, Oncologic Center, Paracelsus Medical University Salzburg, Müllner Hauptstraße 48, A-5020, Salzburg, Austria.
In favor of their outgrowth, cancer cells must resist immune surveillance and edit the immune response. Cancer immunoediting is characterized by fundamental changes in the cellular composition and the inflammatory cytokine profiles in the microenvironment of the primary tumor and metastatic niches, with an ever increasing complexity of interactions between tumor cells and the immune system. Recent data suggest that genetic instability and immunoediting are not necessarily disparate processes. Read More
Background: Cell migration including collective cell movement and individual cell migration are crucial factors in embryogenesis. During the spreading/migration of cells, several types of adhesive structures physically interacting with the extracellular matrix (ECM) or with another cell have been described and the formation and maturation of adhesion structures are coordinated, however the molecular pathways involved are still not fully understood.
Results: We generated a mouse embryonic fibroblast line (MEF) from homozygous mutant (Hectd1 (R/R) , Hectd1 (Gt(RRC200)) ) mouse of the E3 ubiquitin ligase for inhibin B receptor (Hectd1). Read More
Cell Commun Signal 2017 Jan 5;15(1). Epub 2017 Jan 5.
Laboratory for Immunological and Molecular Cancer Research, Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Paracelsus Medical University, Müllner Hauptstrasse 48, Salzburg, 5020, Austria.
The immune system is capable of distinguishing between danger- and non-danger signals, thus inducing either an appropriate immune response against pathogens and cancer or inducing self-tolerance to avoid autoimmunity and immunopathology. One of the mechanisms that have evolved to prevent destruction by the immune system, is to functionally silence effector T cells, termed T cell exhaustion, which is also exploited by viruses and cancers for immune escape In this review, we discuss some of the phenotypic markers associated with T cell exhaustion and we summarize current strategies to reinvigorate exhausted T cells by blocking these surface marker using monoclonal antibodies. Read More
Recent studies have demonstrated that the bacterial chaperone and serine protease high temperature requirement A (HtrA) is closely associated with the establishment and progression of several infectious diseases. HtrA activity enhances bacterial survival under stress conditions, but also has direct effects on functions of the cell adhesion protein E-cadherin and extracellular matrix proteins, including fibronectin and proteoglycans. Although HtrA cannot be considered as a pathogenic factor per se, it exhibits favorable characteristics making HtrA a potentially attractive drug target to combat various bacterial infections. Read More
Cell Commun Signal 2017 Jan 5;15(1). Epub 2017 Jan 5.
Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center of Kidney Diseases, Beijing, 100853, People's Republic of China.
Background: Uric acid (UA) is an antioxidant found in human serum. However, high UA levels may also have pro-oxidant functions. According to previous research, aldose reductase (AR) plays a vital role in the oxidative stress-related complications of diabetes. Read More
Background: STAT3 is increasingly becoming known for its non-transcriptional regulation of mitochondrial bioenergetic function upon activation of its S727 residue (S727-STAT3). Lengthy mitochondrial dysfunction can lead to cell death. We tested whether an integrin-FAK-STAT3 signaling pathway we recently discovered regulates mitochondrial function and cell survival, and treatments thereof. Read More
Background: Some herpesviruses like human cytomegalovirus (HCMV) encode viral G protein-coupled receptors that cause reprogramming of cell signaling to facilitate dissemination of the virus, prevent immune surveillance and establish life-long latency. Human GPCRs are known to function in complex signaling networks involving direct physical interactions as well as indirect crosstalk of orthogonal signaling networks. The human chemokine receptor CXCR4 is expressed on hematopoietic stem cells, leukocytes, endothelial and epithelial cells, which are infected by HCMV or display reservoirs of latency. Read More
Background: The serine proteases HtrA/DegP secreted by the human gastrointestinal pathogens Helicobacter pylori (H. pylori) and Campylobacter jejuni (C. jejuni) cleave the mammalian cell adhesion protein E-cadherin to open intercellular adhesions. Read More
Cell Commun Signal 2016 12 1;14(1):29. Epub 2016 Dec 1.
National Animal Transmissible Spongiform Encephalopathy Laboratory and key Laboratory of Animal and Zoonosis of Ministry Agriculture, College of Veterinary Medicine and State key Laboratory of Agrobiotechnology, China Agricultural University, Beijing, 100193, People's Republic of China.
Mycobacterium avium subsp. paratuberculosis (MAP) is an intracellular pathogen and is the causative agent of Johne's disease of domestic and wild ruminants. Johne's disease is characterized by chronic granulomatous enteritis leading to substantial economic losses to the livestock sector across the world. Read More
Background: Squamous cell carcinoma of the tongue (tongue SCC) is a major subtype of head and neck squamous cell carcinoma (HNSCC), which is an intractable cancer under current therapeutics. ARF6 and its effector AMAP1 are often overexpressed in different types of cancers, such as breast cancer and renal cancer, and in these cancers, AMAP1 binds to EPB41L5 to promote invasion, metastasis, and drug resistance. EPB41L5 is a mesenchymal-specific protein, normally induced during epithelial-mesenchymal transition (EMT) to promote focal adhesion dynamics. Read More
Cell Commun Signal 2016 11 4;14(1):27. Epub 2016 Nov 4.
Laboratorio de Microscopia Aplicada a Estudios Moleculares y Celulares, Facultad de Ingeniería (Bioingeniería-Bioinformática), Universidad Nacional de Entre Ríos, Ruta 11, Km 10, Oro Verde, Entre Ríos, Argentina.
The establishment, remodeling and maintenance of tissular architecture during animal development, and even across juvenile to adult life, are deeply regulated by a delicate interplay of extracellular signals, cell membrane receptors and intracellular signal messengers. It is well known that cell adhesion molecules (cell-cell and cell-extracellular matrix) play a critical role in these processes. Particularly, adherens junctions (AJs) mediated by E-cadherin and catenins determine cell-cell contact survival and epithelia function. Read More
Background: Chemokines and their receptors play a decisive role in tumor progression and metastasis. We recently found a new signaling mechanism in malignant glioma cells mediated by transmembrane chemokines that we termed "inverse signaling". According to this hypothesis, soluble (s)-CXCL16 binds to the surface-expressed transmembrane (tm) -CXCL16, and induces signaling and different biological effects in the stimulated cells, so that the transmembrane ligand itself acts as a receptor for its soluble counterpart. Read More
Cell Commun Signal 2016 10 21;14(1):25. Epub 2016 Oct 21.
Women's Cancer Research Center, Department of Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute, Magee Women's Research Institute, 204 Craft Avenue, Room A412, Pittsburgh, PA, 15213, USA.
Background: ErbB2 Receptor Tyrosine Kinase 2 (ErbB2, HER2/Neu) is amplified in breast cancer and associated with poor prognosis. Growing evidence suggests interplay between ErbB2 and insulin-like growth factor (IGF) signaling. For example, ErbB2 inhibitors can block IGF-induced signaling while, conversely, IGF1R inhibitors can inhibit ErbB2 action. Read More
Non-protein coding RNAs in different flavors (miRNAs, piRNAs, snoRNAs, lncRNAs, SHOT-RNAs), exosomes, large oncosomes, exoDNA and now tumor-educated platelets (TEPs) have emerged as crucial signal transmitting, transporting and regulating devices of cells in the last two decades. They are also establishing themselves increasingly in the realm of tumor research. We are currently witnessing a mushrooming of candidate entities for diagnostic and prognostic cancer detection and characterization tests that could have a major impact on how this diverse group of diseases is initially spotted and subsequently treated in the near future. Read More
Background: Reports of exocrine-to-endocrine reprogramming through expression or stabilization of the transcription factor neurogenin 3 (NGN3) have generated renewed interest in harnessing pancreatic plasticity for therapeutic applications. NGN3 is expressed by a population of endocrine progenitor cells that give rise exclusively to hormone-secreting cells within pancreatic islets and is necessary and sufficient for endocrine differentiation during development. In the adult human pancreas, NGN3 is expressed by dedifferentiating exocrine cells with a phenotype resembling endocrine progenitor cells and the capacity for endocrine differentiation in vitro. Read More
Under physiological conditions, endothelial cells and the endothelial nitric oxide (NO) synthase (eNOS) are the main source of NO in the cardiovascular system. However, several other cell types have also been implicated in the NO-dependent regulation of cell function, including erythrocytes. NO derived from red blood cells has been proposed to regulate erythrocyte membrane fluidity, inhibit platelet activation and induce vasodilation in hypoxic areas, but these proposals are highly controversial. Read More
Background: Vasodilator-Stimulated Phosphoprotein (VASP) is involved in the inhibition of agonist-induced platelet aggregation by cyclic nucleotides and the adhesion of platelets to the vascular wall. αIIbβ3 is the main integrin responsible for platelet activation and Rap1b plays a key role in integrin signalling. We investigated whether VASP is involved in the regulation of Rap1b in platelets since VASP-null platelets exhibit augmented adhesion to endothelial cells in vivo. Read More
Tumor development and tumor progression is not only determined by the corresponding tumor cells but also by the tumor microenvironment. This includes an orchestrated network of interacting cell types (e.g. Read More
Background: Tyro3, Axl, and Mertk (TAMs) are a family of three conserved receptor tyrosine kinases that have pleiotropic roles in innate immunity and homeostasis and when overexpressed in cancer cells can drive tumorigenesis.
Methods: In the present study, we engineered EGFR/TAM chimeric receptors (EGFR/Tyro3, EGFR/Axl, and EGF/Mertk) with the goals to interrogate post-receptor functions of TAMs, and query whether TAMs have unique or overlapping post-receptor activation profiles. Stable expression of EGFR/TAMs in EGFR-deficient CHO cells afforded robust EGF inducible TAM receptor phosphorylation and activation of downstream signaling. Read More
Cell Commun Signal 2016 08 31;14(1):18. Epub 2016 Aug 31.
Molecular Pathogenesis Group, National Toxicology Program (NTP) Laboratory, Division of the NTP (DNTP), National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), U.S. Department of Health and Human Services (HHS), Research Triangle Park, North Carolina, 27709, USA.
Background: The phytoestrogen, genistein at low doses nongenomically activates mitogen-activated protein kinase p44/42 (MAPKp44/42) via estrogen receptor alpha (ERα) leading to proliferation of human uterine leiomyoma cells. In this study, we evaluated if MAPKp44/42 could activate downstream effectors such as mitogen- and stress-activated protein kinase 1 (MSK1), which could then epigenetically modify histone H3 by phosphorylation following a low dose (1 μg/ml) of genistein.
Results: Using hormone-responsive immortalized human uterine leiomyoma (ht-UtLM) cells, we found that genistein activated MAPKp44/42 and MSK1, and also increased phosphorylation of histone H3 at serine10 (H3S10ph) in ht-UtLM cells. Read More
Background: CASKIN2 is a homolog of CASKIN1, a scaffolding protein that participates in a signaling network with CASK (calcium/calmodulin-dependent serine kinase). Despite a high level of homology between CASKIN2 and CASKIN1, CASKIN2 cannot bind CASK due to the absence of a CASK Interaction Domain and consequently, may have evolved undiscovered structural and functional distinctions.
Results: We demonstrate that the crystal structure of the Sterile Alpha Motif (SAM) domain tandem (SAM1-SAM2) oligomer from CASKIN2 is different than CASKIN1, with the minimal repeating unit being a dimer, rather than a monomer. Read More