A5018626606- Cancer-related Molecular Pathways
- Monoclonal and Polyclonal Antibodies Research
- Microtubule and mitosis dynamics
- T-cell and B-cell Immunology
- Cell Adhesion Molecules Research
- Immune Cell Function and Interaction
- Cancer, Hypoxia, and Metabolism
- Ubiquitin and proteasome pathways
- Protein Kinase Regulation and GTPase Signaling
- Cancer, Lipids, and Metabolism
- Ovarian cancer diagnosis and treatment
- Metabolism, Diabetes, and Cancer
- RNA modifications and cancer
- Peptidase Inhibition and Analysis
- CAR-T cell therapy research
- NF-κB Signaling Pathways
- Cancer-related molecular mechanisms research
- Cytokine Signaling Pathways and Interactions
- PARP inhibition in cancer therapy
- Viral Infectious Diseases and Gene Expression in Insects
- PI3K/AKT/mTOR signaling in cancer
- Signaling Pathways in Disease
- Protein Degradation and Inhibitors
- Galectins and Cancer Biology
- ATP Synthase and ATPases Research
Goethe University Frankfurt
2009-2024
University Hospital Frankfurt
2018-2023
University of Cambridge
2009-2014
Universität Hamburg
2013
University Medical Center Hamburg-Eppendorf
2013
R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology
2009
Leiden University Medical Center
2009
Imperial College London
2008
Hammersmith Hospital
2008
Harvard University
1994-2001
The molecular adapter Fyb/Slap regulates signaling downstream of the T cell receptor (TCR), but whether it plays a positive or negative role is controversial. We demonstrate that Fyb/Slap-deficient cells exhibit defective proliferation and cytokine production in response to TCR stimulation. also required vivo for cell-dependent immune responses. Functionally, has no apparent activation known pathways, F-actin polymerization, clustering. Rather, TCR-induced integrin clustering adhesion. Thus,...
TcRζ/CD3 ligation initiates a signaling cascade involving CD4/CD8-p56 lck , p59 fyn and ZAP-70, as well lymphoid downstream proteins VAV, SLP-76, FYB/SLAP. A current question concerns the nature of binding partner(s) FYB in T cells. In this study, using two-hybrid screen with bait, we have identified eight clones, four which correspond to recently published protein SKAP55, two related some 44% homology SKAP55 (termed SKAP55-related protein, SKAP55R). The clones showed only minor differences...
Concomitant inhibition of anaplastic lymphoma kinase (ALK) and bromodomain-4 (BRD4) is a potential therapeutic strategy for targeting two key oncogenic drivers that co-segregate in significant fraction high-risk neuroblastoma patients, mutation ALK amplification MYCN. Starting from known dual polo-like (PLK)-1–BRD4 inhibitor BI-2536, we employed structure-based design to redesign this series toward compounds with ALK–BRD4 profile. These efforts led compound...
Salt-inducible kinases (SIKs) are key metabolic regulators. The imbalance in SIK function is associated with the development of diverse cancers, including breast, gastric, and ovarian cancers. Chemical tools to clarify roles different diseases are, however, sparse generally characterized by poor kinome-wide selectivity. Here, we have adapted pyrido[2,3-d]pyrimidin-7-one-based p21-activated kinase (PAK) inhibitor G-5555 for targeting SIK, exploiting differences back-pocket region these...
CD5 is a T-cell-specific antigen which binds to the B-cell CD72 and acts as coreceptor in stimulation of T-cell growth. associates with receptor zeta chain (TcR zeta)/CD3 complex rapidly phosphosphorylated on tyrosine residues result TcR zeta/CD3 ligation. However, despite this, mechanism by generates intracellular signals unclear. In this study, we demonstrate that coupled protein-tyrosine kinase p56lck can act substrate for p56lck. Coexpression baculovirus expression system resulted...
ERK 1/2 are found to be hyperactive in many cancers. Active (pERK 1/2) known protect cancer cells from undergoing death receptor‐mediated apoptosis, although the mechanism(s) behind this is poorly understood. Through vitro kinase assays and mass‐spectrometry we demonstrate that pERK can phosphorylate pro‐Caspase‐8 at S387. Also, EGFR‐overexpressing Type I II ovarian breast cell lines respectively, remain active only during interphase. During period, could inhibit Trail‐induced most...
Abstract Background The cellular tumor protein p53 ( TP53 ) is a suppressor gene that frequently mutated in human cancers. Among various cancer types, the very aggressive high‐grade serous ovarian carcinoma (HGSOC) exhibits highest prevalence of mutations, present >96% cases. Despite intensive efforts to reactivate p53, no clinical drug has been approved rescue function. In this study, our primary objective was administer vitro‐transcribed (IVT) wild‐type (WT) p53‐mRNA HGSOC cell lines,...
T-cell activation involves the participation of protein-tyrosine kinases p56<sup>lck</sup> and ZAP-70/SYK as well lymphoid proteins such SLP-76 FYB/SLAP. FYB/SLAP has hallmarks an adaptor protein that binds to SH2 domains Src kinase FYN-T SLP-76. Whereas two forms FYB at 120 130 kDa have been identified biochemically, a cDNA encoding only lower molecular weight isoform cloned (termed FYB-120 or SLAP-130). In this study, we report isolation alternative with mass (FYB-130) same structure...
AbstractThe transcriptional cofactor FHL2 interacts with a broad variety of transcription factors and its expression is often deregulated in various types cancer. Here we analyzed for the first time molecular function breast overexpressed almost all human mammary carcinoma samples tested but not normal tissues only low levels were present four premalignant ductal situ (DCIS). Cell cycle analysis revealed an upregulation endogenous towards G2/M MDA-MB 231 cells accelerated transition when was...
SLP-76 (Src homology (SH) 2-domain-containing leukocyte protein of 76 kDa) and FYB/SLAP (FYN-T-binding protein/SLP-76-associated protein) are two hemopoietic cell-specific adaptor proteins downstream TCR-activated tyrosine kinases. has been implicated as an essential component in T cell signaling. FYB is selectively phosphorylated by FYN-T, providing a template for the recruitment FYN-T SH2 domains. Coexpression FYB, can synergistically up-regulate IL-2 production cells upon TCR ligation. In...
The activity of the Salt inducible kinase 2 (SIK2), a member AMP-activated protein (AMPK)-related family, has been linked to several biological processes that maintain cellular and energetic homeostasis. SIK2 is overexpressed in cancers, including ovarian cancer, where it promotes proliferation metastases. Furthermore, as centrosome kinase, shown regulate G2/M transition, its depletion sensitizes cancer paclitaxel-based chemotherapy. Here, we report consequences inhibition on mitosis...
Ovarian cancer exhibits the highest mortality rate among gynecological malignancies. Antimitotic agents, such as paclitaxel, are frontline drugs for treatment of ovarian cancer. They inhibit microtubule dynamics and their efficiency relies on a prolonged mitotic arrest strong activation spindle assembly checkpoint (SAC). Although cancers respond well to clinical efficacy is limited due an early onset drug resistance, which may rely compromised mitosis exit associated with weakend intrinsic...
Abstract Polo-like kinase 1 (PLK1) is a crucial regulator of cell cycle progression. It established that the activation PLK1 depends on coordinated action Aurora-A and Bora. Nevertheless, very little known about spatiotemporal regulation during G2, specifically, mechanisms keep cytoplasmic inactive until shortly before mitosis onset. Here, we describe dimerization as new mechanism controls activation. During early G2 phase, Bora supports transient dimerization, thus fine-tuning timely...
The adaptor protein Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76) plays a crucial role in T cell activation by linking antigen receptor (T receptor, TCR) signals to downstream pathways. At its N terminus, SLP-76 has three key tyrosines (Tyr-113, Tyr-128, and Tyr-145, "3Y") as well sterile α motif (SAM) domain whose function is unclear. We showed previously that the SAM two binding regions mediate dimer oligomer formation. In this study, we have identified...
Cervical cancer is the fourth most frequently diagnosed and fatal gynecological cancer. 15-61% of all cases metastasize develop chemoresistance, reducing 5-year survival cervical patients to as low 17%. Therefore, unraveling mechanisms contributing metastasis critical in developing better-targeted therapies against it. Here, we have identified a novel mechanism where nuclear Caspase-8 directly interacts with inhibits activity CDK9, thereby modulating RNAPII-mediated global transcription,...
While the adaptor SKAP-55 mediates LFA-1 adhesion on T-cells, it is not known whether regulates other aspects of signaling. could potentially act as a node to coordinate modulation with downstream In this regard, GTPase p21ras and extracellular signal-regulated kinase (ERK) pathway play central roles in T-cell function. study, we report that has opposing effects activation -ERK T-cells. deficient primary T-cells showed defect concurrent hyper-activation ERK relative wild-type cells. RNAi...
Ovarian cancer (OC) accounts for approximately 4% of deaths in women worldwide and is the deadliest gynecologic malignancy. High-grade serous ovarian (HGSOC) most predominant cancer, which BRCA1/2 gene mutation ranges from 3 to 27%. PARP inhibitors (PARPi) have shown promising results as a synthetically lethal therapeutic approach BRCA mutant recurrent OC clinical use. However, emerging data indicate that BRCA-deficient cancers may be resistant PARPi, mechanisms this resistance remain...
Abstract Background Recent studies revealed that maternal and embryonic contributions impact on HLA‐G protein expression might contribute to pregnancy success or failure. The main objective of this study was examine the paternal levels immunoregulatory soluble human leukocyte antigen‐G (sHLA‐G) in seminal plasma testicular biopsy samples during artificial reproductive technique (ART) treatment investigate possible correlations with other semen parameters, age, outcome female partner. Methods...