A5032366196- Neurofibromatosis and Schwannoma Cases
- Hippo pathway signaling and YAP/TAZ
- Neuroblastoma Research and Treatments
- Cancer-related Molecular Pathways
- Protein Kinase Regulation and GTPase Signaling
- RNA modifications and cancer
- Wnt/β-catenin signaling in development and cancer
- Cell death mechanisms and regulation
- Pancreatic and Hepatic Oncology Research
- Epigenetics and DNA Methylation
- PI3K/AKT/mTOR signaling in cancer
- Kruppel-like factors research
- Cancer-related gene regulation
- Cancer, Hypoxia, and Metabolism
- Sarcoma Diagnosis and Treatment
- MicroRNA in disease regulation
- Peptidase Inhibition and Analysis
- Cancer-related molecular mechanisms research
- Cytokine Signaling Pathways and Interactions
- Cellular Mechanics and Interactions
- Adrenal and Paraganglionic Tumors
- Pancreatic function and diabetes
- Ubiquitin and proteasome pathways
- Axon Guidance and Neuronal Signaling
- Neurobiology and Insect Physiology Research
Molecular Oncology (United States)
2013-2024
Moffitt Cancer Center
2021-2024
The Wistar Institute
2005-2023
Carnegie Institution for Science
2023
Scripps Research Institute
2012-2021
Ospedale Maggiore
2013
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
2013
Sylvester Comprehensive Cancer Center
2013
Cancer Research Institute
2013
École Polytechnique Fédérale de Lausanne
2010-2013
Membrane-bound proteases have recently emerged as critical mediators of tumorigenesis, angiogenesis, and metastasis. However, the mechanisms by which they regulate these processes remain unknown. As cell surface serine protease fibroblast activation protein (FAP) is selectively expressed on tumor-associated fibroblasts pericytes in epithelial tumors, we set out to investigate role FAP mouse models epithelial-derived solid tumors. In this study, demonstrate that genetic deletion pharmacologic...
Death-associated protein (DAP)-kinase is a calcium/calmodulin regulated serine/threonine kinase that carries ankyrin repeats, death domain, and localized to the cytoskeleton. Here, we report this involved in tumor necrosis factor (TNF)-alpha Fas-induced apoptosis. Expression of DAP-kinase antisense RNA protected cells from killing by anti-Fas/APO-1 agonistic antibodies. Deletion domain abrogated apoptotic functions kinase, thus, documenting for first time importance domain. Overexpression...
The <i>Nf2</i> tumor suppressor gene product merlin is related to the membrane-cytoskeleton linker proteins of band 4.1 superfamily, including ezrin, radixin, and moesin (ERMs). Merlin regulated by phosphorylation in a Rac/cdc42-dependent fashion. We report that at serine 518 induced p21-activated kinase PAK2. This demonstrated biochemical fractionation, use active dominant-negative mutants PAK2, immunodepletion. By using wild-type mutated forms phospho-directed antibodies, we show leads...
A strategy for targeting protein kinases with large ATP-binding sites by using bulky and rigid octahedral ruthenium complexes as structural scaffolds is presented. highly potent selective GSK3 Pim1 half-sandwich complex NP309 was successfully converted into a PAK1 inhibitor making use of the compounds Λ-FL172 Λ-FL411 in which cyclopentadienyl moiety replaced chloride sterically demanding diimine ligands. 1.65 Å cocrystal structure reveals how coordination sphere matches size active site...
The Hippo-Yap signaling pathway regulates a number of developmental and adult cellular processes, including cell fate determination, tissue growth, tumorigenesis. Members the scaffold protein angiomotin (Amot) family interact with several Hippo components, Yap (Yes-associated protein), either stimulate or inhibit activity. We used combination genetic, biochemical, transcriptional approaches to assess functional consequences Amot-Yap interaction in mice human cells. Mice liver-specific Amot...
Abstract Given the prevalence of Ras mutations in human cancer, it is critical to understand effector pathways downstream oncogenic leading transformation. To directly assess requirement for Rac1 K-ras–induced tumorigenesis, we employed a model lung cancer which an allele K-ras could be activated by Cre-mediated recombination presence or absence conditional deletion Rac1. We show that function required tumorigenesis this model. Furthermore, although alone was compatible with cell viability...
The development of the embryonic vascular system into a highly ordered network requires precise control over migration and branching endothelial cells (ECs). We have previously identified angiomotin (Amot) as receptor for angiogenesis inhibitor angiostatin. Furthermore, DNA vaccination targeting Amot inhibits tumor growth. However, little is known regarding role in physiological angiogenesis. therefore investigated neovascularization during zebrafish mouse embryogenesis. Here we report that...
Abstract K-ras is the most commonly mutated oncogene in pancreatic cancer and its activation murine models sufficient to recapitulate spectrum of lesions seen human ductal adenocarcinoma (PDAC). Recent studies suggest that Notch receptor signaling becomes reactivated a subset PDACs, leading hypothesis Notch1 functions as an this setting. To determine whether required for K-ras–induced tumorigenesis, we used mouse model which oncogenic allele activated deleted simultaneously pancreas....
Non-small cell lung cancer (NSCLC) is the leading cause of deaths worldwide. The oxygen-sensitive hypoxia inducible factor (HIF) transcriptional regulators HIF-1α and HIF-2α are overexpressed in many human NSCLCs, constitutive activity can promote murine tumor progression, suggesting that HIF proteins may be effective NSCLC therapeutic targets. To investigate consequences inhibiting cancers, we deleted Hif-1 α or Hif-2 an established Kras G12D -driven model. Deletion had no obvious effect on...
Background:The PAKs are effectors of Rac/cdc42.Results: Identification a pyridopyrimidinone, as potent inhibitor the group I that shows anti-tumor activity in vivo.Conclusion: A pyridopyrimidinone provides scaffold for development high specificity PAK inhibitors.Significance: class orally available ATP-competitive Group inhibitors with significant potential treatment NF2.The p21-activated kinases (PAKs) immediate downstream Rac/Cdc42 small G-proteins and implicated promoting tumorigenesis...
Abstract The Notch pathway has been implicated in a number of malignancies with different roles that are cell- and tissue-type dependent. Notch1 is putative oncogene non–small cell lung cancer (NSCLC) activation the represents negative prognostic factor. To establish role adenocarcinoma, we directly assessed its requirement Kras-induced tumorigenesis vivo using an autochthonous model adenocarcinoma concomitant expression oncogenic Kras deletion Notch1. We found function required for tumor...
In this study we describe the identification and structure-function analysis of a novel death-associated protein (DAP) kinase-related protein, DRP-1. DRP-1 is 42-kDa Ca2+/calmodulin (CaM)-regulated serine threonine kinase which shows high degree homology to DAP kinase. The region spans catalytic domain CaM-regulatory region, whereas remaining C-terminal part differs completely from displays no any known protein. also homologous recently identified ZIP lesser extent domains DRAK1 -2. Thus,...
Caspr and Caspr2 regulate the formation of distinct axonal domains around nodes Ranvier. is required for generation a membrane barrier at paranodal junction (PNJ), whereas serves as scaffold that clusters Kv1 channels juxtaparanodal region (JXP). Both interact with protein 4.1B, which may link adhesion complexes to cytoskeleton. To determine role 4.1B in function proteins, we examined ability transgenic mutants lacking their 4.1-binding sequence (d4.1) restore channel clustering - -null...
The Hippo-YAP pathway is a central regulator of cell contact inhibition, proliferation and death. There are conflicting reports regarding the role Angiomotin (Amot) in regulating this pathway. While some studies suggest YAP-inhibitory function other indicate Amot required for YAP activity. Here, we describe an Amot-dependent complex comprised Amot, Merlin. phosphorylation at Serine 176 shifts localization to plasma membrane, where it associates with tight-junction proteins Pals1/PATJ...
Abstract The Hippo pathway regulates cell proliferation and organ size through control of the transcriptional regulators YAP (yes-associated protein) TAZ. Upon extracellular stimuli such as cell–cell contact, negatively cytoplasmic sequestration. Under conditions low density, is nuclear associates with enhancer regions gene promoters. mainly described a activator genes involved in survival. Using genome-wide approach, we show here that, addition to its known function activator, functions...
Interaction of certain cytokines with their corresponding cell-surface receptors induces programed cell death. Interferon-γ in HeLa cells a type death features characteristic Here, we report the isolation novel gene, DAP3 (death-associated protein-3), involved mediating interferon-γ-induced The rescue this gene was performed by functional selection approach cloning that is based on transfection an antisense cDNA expression library. RNA-mediated inactivation protected from This property...