A5101858270- HER2/EGFR in Cancer Research
- Immune Cell Function and Interaction
- Estrogen and related hormone effects
- Computational Drug Discovery Methods
- T-cell and B-cell Immunology
- Ubiquitin and proteasome pathways
- NF-κB Signaling Pathways
- Immunotherapy and Immune Responses
- Immune Response and Inflammation
- Monoclonal and Polyclonal Antibodies Research
- Cancer Cells and Metastasis
- Cellular transport and secretion
- Cancer-related Molecular Pathways
- T-cell and Retrovirus Studies
- Wnt/β-catenin signaling in development and cancer
- Vector-Borne Animal Diseases
- Acute Myeloid Leukemia Research
- Animal Disease Management and Epidemiology
- Cytokine Signaling Pathways and Interactions
- Epigenetics and DNA Methylation
- Glycosylation and Glycoproteins Research
- Sperm and Testicular Function
- DNA Repair Mechanisms
- Protein Kinase Regulation and GTPase Signaling
- Cell Image Analysis Techniques
University of Nebraska Medical Center
2009-2018
Nebraska Medical Center
2012
NorthShore University HealthSystem
2007-2012
Northwestern University
2007-2012
University of Nebraska at Omaha
2011
Molecular Oncology (United States)
2007-2008
National Institute of Allergy and Infectious Diseases
2001-2006
National Institutes of Health
1998-2006
Cleveland Clinic
2003-2004
NewYork–Presbyterian Hospital
2001
Hematopoietic stem cells (HSCs) are heterogeneous with respect to their self-renewal, lineage, and reconstitution potentials. Although c-Kit is required for HSC function, gain loss-of-function mutants suggest that even small changes in signaling profoundly affect function. Herein, we demonstrate the most rigorously defined HSCs can be separated into functionally distinct subsets based on activity. Functional transcriptome studies show low levels of surface expression (c-Kit(lo)) exhibit...
Cbl is the product of protooncogene c- cbl and involved in T cell antigen receptor (TCR)-mediated signaling. To understand role for immune system development function, we generated a Cbl-deficient mouse strain. In mice, positive selection thymocytes expressing major histocompatibility complex class II-restricted transgenic TCR was significantly enhanced. Two factors may have contributed to altered thymic selection. First, deficiency markedly up-regulated activity ZAP-70 mitogen-activated...
Ligand-induced down-regulation controls the signaling potency of epidermal growth factor receptor (EGFR/ErbB1). Overexpression studies have identified Cbl-mediated ubiquitinylation EGFR as a mechanism ligand-induced down-regulation. However, role endogenous Cbl in and precise step endocytic pathway regulated by remain unclear. Using Cbl–/– mouse embryonic fibroblast cell lines, we demonstrate that is essential for efficient degradation EGFR. Further analyses using Chinese hamster ovary cells...
The Piwi pathway is deeply conserved amongst animals because one of its essential functions to repress transposons. However, many Piwi-interacting RNAs (piRNAs) do not base-pair transposons and remain mysterious in their targeting function. sheer number piRNA cluster (piC) loci animal genomes infrequent sequence conservation also present challenges determining which piC are most important for development. To address this question, we determined the expression patterns across a wide...
Tumor necrosis factor (TNF)-related activation-induced cytokine (TRANCE) is a TNF family member essential for osteoclast differentiation, and it induces the activation survival of osteoclasts mature dendritic cells. We recently demonstrated that TRANCE activates Akt via mechanism involving receptor (TRANCE-R)/RANK, TRAF6, c-Src. Here, we show TRANCE-R CD40 recruit Cbl family-scaffolding proteins, phospholipid kinase phosphatidylinositol 3-kinase in ligand-dependent manner. The recruitment...
Abstract Activation of T cells usually requires two signals. Signal 1 is mediated via a peptide-MHC on the APC; signal 2 costimulatory molecule APC surface. We demonstrate here that naive CD4+ actually acquire CD80 (B7-1) from syngeneic APCs after activation. This phenomenon was demonstrated showing acquisition by CD80/CD86 (B7-2) knockout mice, and treating with cyclohexamide to further rule out endogenous expression cells. Moreover, no mRNA could be detected in had acquired CD80. The...
Abstract Epidermal growth factor receptor (EGFR), a member of the ErbB family tyrosine kinases, is overexpressed in as many 60% cases breast and other cancers. EGFR overexpression characteristic highly aggressive molecular subtypes cancer with basal-like BRCA1 mutant phenotypes distinct from ErbB2-overexpressing Yet, substantially weaker compared ErbB2 promoting oncogenic transformation nontumorigenic human mammary epithelial cells (human MEC), suggesting role for cooperating oncogenes....
Active Src localization at focal adhesions (FAs) is essential for cell migration. How this pool linked mechanistically to the large of late endosomes (LEs)/lysosomes (LY) not well understood. Here, we used inducible Tsg101 gene deletion, TSG101 knockdown, and dominant-negative VPS4 expression demonstrate that activated cellular viral FAs requires endosomal-sorting complexes required transport (ESCRT) pathway. deletion also led impaired Src-dependent activation STAT3 adhesion kinase reduced...
AbstractErbB2 (or Her2/Neu) overexpression in breast cancer signifies poorer prognosis, yet it has provided an avenue for targeted therapy as demonstrated by the success of humanized monoclonal antibody Trastuzumab (Herceptin). Resistance to and eventual failure most cases, however, necessitate alternate ErbB2-targeted therapies. HSP90 inhibitors such 17-allylaminodemethoxygeldanamycin (17-AAG), potently downregulate cell surface ErbB2. While precise mechanisms or 17-AAG action remain...
Abstract Background The C-terminal Eps15 homology domain-containing protein 1 (EHD1) is ubiquitously expressed and regulates the endocytic trafficking recycling of membrane components several transmembrane receptors. To elucidate function EHD1 in mammalian development, we generated Ehd1 -/- mice using a Cre/ loxP system. Results Both male female survived at sub-Mendelian ratios. A proportion were viable showed smaller size birth, which continued into adulthood. adult males infertile...
The non-receptor tyrosine kinase Src and receptor epidermal growth factor (EGFR/ErbB1) have been established as collaborators in cellular signaling their combined dysregulation plays key roles human cancers, including breast cancer. In part due to the complexity of biochemical network associated with regulation these proteins well functions, role EGFR remains unclear. Herein we present a new comprehensive, multi-scale dynamical model ErbB signal transduction mammary epithelial cells. This...
The Human Epidermal Growth Factor Receptor 2 (Her2, ErbB2 or Neu) is overexpressed in about 20 - 25% of breast cancers and causally linked to oncogenesis, providing opportunities for targeted therapy. Trastuzumab (Herceptin(™), Genentech Inc, San Francisco, CA), a humanized monoclonal antibody against ErbB2, successful example this concept has vastly improved the response treatment overall survival majority ErbB2+ cancer patients. However, lack some patients as well relapse during course...
Casitas B-cell lymphoma (Cbl)-family E3 ubiquitin ligases are negative regulators of tyrosine kinase signaling. Recent work has revealed a critical role Cbl in the maintenance hematopoietic stem cell (HSC) homeostasis, and mutations CBL have been identified myeloid malignancies. Here we show that, contrast to or Cbl-b single-deficient mice, concurrent loss HSC compartment leads an early-onset lethal myeloproliferative disease mice. Cbl, double-deficient bone marrow cells hypersensitive...
The E3 ubiquitin ligase Casitas B lymphoma protein (Cbl) controls the ubiquitin-dependent degradation of EGF receptor (EGFR), but its role in regulating downstream signaling elements with which it associates and impact on biological outcomes EGFR are less clear. Here, we demonstrate that stimulation human mammary epithelial cells disrupts adherens junctions (AJs) through Vav2 Rac1/Cdc42 activation. In EGF-stimulated cells, Cbl regulates levels phosphorylated thereby attenuating activity....
Eps15 Homology Domain-containing 3 (EHD3), a member of the EHD protein family that regulates endocytic recycling, is first reported to be specifically expressed in glomerular endothelium kidney; therefore we generated Ehd3–/– mice and assessed renal development pathology. animals showed no overt defects, exhibited proteinuria or However, as expression EHD4, related member, was elevated suggested functional compensation, analyzed Ehd3–/–; Ehd4–/– mice. These were smaller, possessed smaller...
Mayumi Naramura 1,2 , Scott Nadeau Bhopal Mohapatra 1,3 Gulzar Ahmad 1 Chandrani Mukhopadhyay Martin Sattler 5 Srikumar M Raja Amarnath Natarajan 1,4 Vimla Band Hamid 1,2,3 Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 2 Department Genetics, Cell Biology Anatomy, College Medicine, 3 Biochemistry & Molecular Biology, 4 Pharmaceutical Sciences, Pharmacy, Dana Farber Institute, Harvard School, Boston, MA Keywords: Cbl, E3 ubiquitin...
Identification and characterization of molecular controls that regulate mammary stem progenitor cell homeostasis are critical to our understanding normal gland development its pathology. We demonstrate conditional knockout Sox9 in the mouse results impaired postnatal development. In short-term lineage tracing using Sox9-CreER driven reporters, marked primarily luminal progenitors bipotent stem/progenitor cells within basal epithelial compartment. contrast, long-term studies Sox9+ precursors...