Tensin-2 interactomics reveals interaction with GAPDH and a phosphorylation-mediated regulatory role in glycolysis.

Integrin adaptor proteins, like tensin-2, are crucial for cell adhesion and signaling. However, the function of tensin-2 beyond localizing to focal adhesions remain poorly understood. We utilized proximity-dependent biotinylation and Strep-tag affinity proteomics to identify interaction partners of tensin-2 in Flp-In 293 T-REx cells.

The Impact of ETV6-NTRK3 Oncogenic Gene Fusions on Molecular and Signaling Pathway Alterations.

Chromosomal translocations creating fusion genes are common cancer drivers. The oncogenic ETV6-NTRK3 (EN) gene fusion joins the sterile alpha domain of the ETV6 transcription factor with the tyrosine kinase domain of the neurotrophin-3 receptor NTRK3. Four EN variants with alternating break points have since been detected in a wide range of human cancers.

Psychedelics promote plasticity by directly binding to BDNF receptor TrkB.

Psychedelics produce fast and persistent antidepressant effects and induce neuroplasticity resembling the effects of clinically approved antidepressants. We recently reported that pharmacologically diverse antidepressants, including fluoxetine and ketamine, act by binding to TrkB, the receptor for BDNF. Here we show that lysergic acid diethylamide (LSD) and psilocin directly bind to TrkB with affinities 1,000-fold higher than those for other antidepressants, and that psychedelics and antidepressants bind to distinct but partially overlapping sites within the transmembrane domain of TrkB dimers.

Deep Immune Profiling of Multiple Myeloma at Diagnosis and under Lenalidomide Maintenance Therapy.

The bone marrow microenvironment interacts with malignant cells and regulates cancer survival and immune evasion in multiple myeloma (MM). We investigated the immune profiles of longitudinal bone marrow samples from patients with newly diagnosed MM ( = 18) using cytometry by time-of-flight. The results before and during treatment were compared between patients with good (GR, = 11) and bad (BR, = 7) responses to lenalidomide/bortezomib/dexamethasone-based treatment.

A multi-omics study to characterize the transdifferentiation of human dermal fibroblasts to osteoblast-like cells.

Various skeletal disorders display defects in osteoblast development and function. An model can help to understand underlying disease mechanisms. Currently, access to appropriate starting material for osteoblastic studies is limited.

Physical and functional interactome atlas of human receptor tyrosine kinases.

Much cell-to-cell communication is facilitated by cell surface receptor tyrosine kinases (RTKs). These proteins phosphorylate their downstream cytoplasmic substrates in response to stimuli such as growth factors. Despite their central roles, the functions of many RTKs are still poorly understood.

SARS-CoV-2-host proteome interactions for antiviral drug discovery.

Treatment options for COVID-19, caused by SARS-CoV-2, remain limited. Understanding viral pathogenesis at the molecular level is critical to develop effective therapy. Some recent studies have explored SARS-CoV-2-host interactomes and provided great resources for understanding viral replication.

Skeletal muscle proteomes reveal downregulation of mitochondrial proteins in transition from prediabetes into type 2 diabetes.

Skeletal muscle insulin resistance is a central defect in the pathogenesis of type 2 diabetes (T2D). Here, we analyzed skeletal muscle proteome in 148 vastus lateralis muscle biopsies obtained from men covering all glucose tolerance phenotypes: normal, impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and T2D. Skeletal muscle proteome was analyzed by a sequential window acquisition of all theoretical mass spectra (SWATH-MS) proteomics technique.

Molecular pathogenesis of rhegmatogenous retinal detachment.

Rhegmatogenous retinal detachment (RRD) is an ophthalmic emergency, which usually requires prompt surgery to prevent further detachment and restore sensory function. Although several individual factors have been suggested, a systems level understanding of molecular pathomechanisms underlying this severe eye disorder is lacking. To address this gap in knowledge we performed the molecular level systems pathology analysis of the vitreous from 127 patients with RRD using state-of-the art quantitative mass spectrometry to identify the individual key proteins, as well as the biochemical pathways contributing to the development of the disease.

Novel Hemizygous IL2RG p.(Pro58Ser) Mutation Impairs IL-2 Receptor Complex Expression on Lymphocytes Causing X-Linked Combined Immunodeficiency.

Hypomorphic IL2RG mutations may lead to milder phenotypes than X-SCID, named variably as atypical X-SCID or X-CID. We report an 11-year-old boy with a novel c. 172C>T;p.

PTPRA Phosphatase Regulates GDNF-Dependent RET Signaling and Inhibits the RET Mutant MEN2A Oncogenic Potential.

The RET proto-oncogene encodes receptor tyrosine kinase, expressed primarily in tissues of neural crest origin. De-regulation of RET signaling is implicated in several human cancers. Recent phosphatome interactome analysis identified PTPRA interacting with the neurotrophic factor (GDNF)-dependent RET-Ras-MAPK signaling-axis.

A β2-Integrin/MRTF-A/SRF Pathway Regulates Dendritic Cell Gene Expression, Adhesion, and Traction Force Generation.

β2-integrins are essential for immune system function because they mediate immune cell adhesion and signaling. Consequently, a loss of β-integrin expression or function causes the immunodeficiency disorders, Leukocyte Adhesion Deficiency (LAD) type I and III. LAD-III is caused by mutations in an important integrin regulator, kindlin-3, but exactly how kindlin-3 regulates leukocyte adhesion has remained incompletely understood.

FGFR4 phosphorylates MST1 to confer breast cancer cells resistance to MST1/2-dependent apoptosis.

Cancer cells balance with the equilibrium of cell death and growth to expand and metastasize. The activity of mammalian sterile20-like kinases (MST1/2) has been linked to apoptosis and tumor suppression via YAP/Hippo pathway-independent and -dependent mechanisms. Using a kinase substrate screen, we identified here MST1 and MST2 among the top substrates for fibroblast growth factor receptor 4 (FGFR4).

Talin-mediated force transmission and talin rod domain unfolding independently regulate adhesion signaling.

Talin protein is one of the key components in integrin-mediated adhesion complexes. Talins transmit mechanical forces between β-integrin and actin, and regulate adhesion complex composition and signaling through the force-regulated unfolding of talin rod domain. Using modified talin proteins, we demonstrate that these functions contribute to different cellular processes and can be dissected.

Release of transcriptional repression via ErbB2-induced, SUMO-directed phosphorylation of myeloid zinc finger-1 serine 27 activates lysosome redistribution and invasion.

HER2/ErbB2 activation turns on transcriptional processes that induce local invasion and lead to systemic metastasis. The early transcriptional changes needed for ErbB2-induced invasion are poorly understood. Here, we link ErbB2 activation to invasion via ErbB2-induced, SUMO-directed phosphorylation of a single serine residue, S27, of the transcription factor myeloid zinc finger-1 (MZF1).

Systems pathology analysis identifies neurodegenerative nature of age-related vitreoretinal interface diseases.

Aging is a phenomenon that is associated with profound medical implications. Idiopathic epiretinal membrane (iEMR) and macular hole (MH) are the major vision-threatening vitreoretinal diseases affecting millions of aging people globally, making these conditions an important public health issue. iERM is characterized by fibrous tissue developing on the surface of the macula, which leads to biomechanical and biochemical macular damage.

An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations.

Protein-protein interactions govern almost all cellular functions. These complex networks of stable and transient associations can be mapped by affinity purification mass spectrometry (AP-MS) and complementary proximity-based labeling methods such as BioID. To exploit the advantages of both strategies, we here design and optimize an integrated approach combining AP-MS and BioID in a single construct, which we term MAC-tag.

Antiviral Properties of Chemical Inhibitors of Cellular Anti-Apoptotic Bcl-2 Proteins.

Viral diseases remain serious threats to public health because of the shortage of effective means of control. To combat the surge of viral diseases, new treatments are urgently needed. Here we show that small-molecules, which inhibit cellular anti-apoptotic Bcl-2 proteins (Bcl-2i), induced the premature death of cells infected with different RNA or DNA viruses, whereas, at the same concentrations, no toxicity was observed in mock-infected cells.

Phosphoproteomics to Characterize Host Response During Influenza A Virus Infection of Human Macrophages.

Influenza A viruses cause infections in the human respiratory tract and give rise to annual seasonal outbreaks, as well as more rarely dreaded pandemics. Influenza A viruses become quickly resistant to the virus-directed antiviral treatments, which are the current main treatment options. A promising alternative approach is to target host cell factors that are exploited by influenza viruses.

Quantitative changes in Gimap3 and Gimap5 expression modify mitochondrial DNA segregation in mice.

Mammalian mitochondrial DNA (mtDNA) is a high-copy maternally inherited genome essential for aerobic energy metabolism. Mutations in mtDNA can lead to heteroplasmy, the co-occurence of two different mtDNA variants in the same cell, which can segregate in a tissue-specific manner affecting the onset and severity of mitochondrial dysfunction. To investigate mechanisms regulating mtDNA segregation we use a heteroplasmic mouse model with two polymorphic neutral mtDNA haplotypes (NZB and BALB) that displays tissue-specific and age-dependent selection for mtDNA haplotypes.

Phosphoproteome characterization reveals that Sendai virus infection activates mTOR signaling in human epithelial cells.

Sendai virus (SeV) is a common respiratory pathogen in mice, rats, and hamsters. Host cell recognition of SeV is mediated by pathogen recognition receptors, which recognize viral components and induce intracellular signal transduction pathways that activate the antiviral innate immune response. Viruses use host proteins to control the activities of signaling proteins and their downstream targets, and one of the most important host protein modifications regulated by viral infection is phosphorylation.

Uncovering surface-exposed antigens of Lactobacillus rhamnosus by cell shaving proteomics and two-dimensional immunoblotting.

The present study reports the identification and comparison of all expressed cell-surface exposed proteins from the well-known probiotic L. rhamnosus GG and a related dairy strain, Lc705. To obtain this information, the cell-surface bound proteins were released from intact cells by trypsin shaving under hypertonic conditions with and without DTT.