Medicine and Health Sciences Commons^™

Germinal Center Reutilization By Newly Activated B Cells., Tanja A Schwickert, Boris Alabyev, Tim Manser, Michel C Nussenzweig

Department of Microbiology and Immunology Faculty Papers

Germinal centers (GCs) are specialized structures in which B lymphocytes undergo clonal expansion, class switch recombination, somatic hypermutation, and affinity maturation. Although these structures were previously thought to contain a limited number of isolated B cell clones, recent in vivo imaging studies revealed that they are in fact dynamic and appear to be open to their environment. We demonstrate that B cells can colonize heterologous GCs. Invasion of primary GCs after subsequent immunization is most efficient when T cell help is shared by the two immune responses; however, it also occurs when the immune responses are entirely unrelated. We conclude …

Il-4(-/-) Mice With Lethal Mesocestoides Corti Infections--Reduced Th2 Cytokines And Alternatively Activated Macrophages., A. E. O'Connell, L. A. Kerepesi, G. L. Vandergrift, D. R. Herbert, T J. Van Winkle, D. C. Hooper, E J. Pearce, D. Abraham

Department of Microbiology and Immunology Faculty Papers

Protection against Mesocestoides corti, a cestode that invades vital organs, is dependent on the production of IL-4, as IL-4(-/-) mice were found to have higher parasite burdens when compared with wild-type mice. The goal of this study was to investigate the role of IL-4 in immunity to M. corti, focusing on the immunological profile and on potential mediators of pathology. IL-4(-/-) mice infected with M. corti showed 100% mortality by 32 days, whereas wild-type mice survived for approximately 1 year. Parasite burdens were significantly increased in the liver, peritoneal, and thoracic cavities of IL-4(-/-) mice, associated with impaired recruitment of …

Mitochondrial Mislocalization Underlies Abeta42-Induced Neuronal Dysfunction In A Drosophila Model Of Alzheimer's Disease., Kanae Iijima-Ando, Stephen A Hearn, Christopher Shenton, Anthony Gatt, Lijuan Zhao, Koichi Iijima

Department of Biochemistry and Molecular Biology Faculty Papers

The amyloid-beta 42 (Abeta42) is thought to play a central role in the pathogenesis of Alzheimer's disease (AD). However, the molecular mechanisms by which Abeta42 induces neuronal dysfunction and degeneration remain elusive. Mitochondrial dysfunctions are implicated in AD brains. Whether mitochondrial dysfunctions are merely a consequence of AD pathology, or are early seminal events in AD pathogenesis remains to be determined. Here, we show that Abeta42 induces mitochondrial mislocalization, which contributes to Abeta42-induced neuronal dysfunction in a transgenic Drosophila model. In the Abeta42 fly brain, mitochondria were reduced in axons and dendrites, and accumulated in the somata without severe mitochondrial …

Regulation Of Energy Stores And Feeding By Neuronal And Peripheral Creb Activity In Drosophila., Koichi Iijima, Lijuan Zhao, Christopher Shenton, Kanae Iijima-Ando

Department of Biochemistry and Molecular Biology Faculty Papers

The cAMP-responsive transcription factor CREB functions in adipose tissue and liver to regulate glycogen and lipid metabolism in mammals. While Drosophila has a homolog of mammalian CREB, dCREB2, its role in energy metabolism is not fully understood. Using tissue-specific expression of a dominant-negative form of CREB (DN-CREB), we have examined the effect of blocking CREB activity in neurons and in the fat body, the primary energy storage depot with functions of adipose tissue and the liver in flies, on energy balance, stress resistance and feeding behavior. We found that disruption of CREB function in neurons reduced glycogen and lipid stores …

Fluorescent Protein Markers To Tag Collagenous Proteins: The Paradigm Of Procollagen Vii, Hye J. Chung, Andrzej Steplewski, Jouni Uitto, Andrzej Fertala

Department of Dermatology and Cutaneous Biology Faculty Papers

Fluorescent proteins are powerful markers allowing tracking expression, intracellular localization, and translocation of tagged proteins but their effects on the structure and assembly of complex extracellular matrix proteins has not been investigated. Here, we analyzed the utility of fluorescent proteins as markers for procollagen VII, a triple-helical protein critical for the integrity of dermal-epidermal junction. DNA constructs encoding a red fluorescent protein-tagged wild type mini-procollagen VII α chain and green fluorescent protein-tagged α chains harboring selected mutations were genetically engineered. These DNA constructs were co-expressed in HEK-293 cells and the assembly of heterogeneous triple-helical mini-procollagen VII molecules was analyzed. Immunoprecipitation …

Reactive Oxygen And Nitrogen Species Induce Protein And Dna Modifications Driving Arthrofibrosis Following Total Knee Arthroplasty., Theresa A Freeman, Javad Parvizi, Craig J Della Valle, Marla J Steinbeck

Department of Orthopaedic Surgery Faculty Papers

BACKGROUND: Arthrofibrosis, occurring in 3%-4% of patients following total knee arthroplasty (TKA), is a challenging condition for which there is no defined cause. The hypothesis for this study was that disregulated production of reactive oxygen species (ROS) and nitrogen species (RNS) mediates matrix protein and DNA modifications, which result in excessive fibroblastic proliferation.

RESULTS: We found increased numbers of macrophages and lymphocytes, along with elevated amounts of myeloperoxidase (MPO) in arthrofibrotic tissues when compared to control tissues. MPO expression, an enzyme that generates ROS/RNS, is usually limited to neutrophils and some macrophages, but was found by immunohistochemistry to be expressed …

Subconjunctivally Implantable Hydrogels With Degradable And Thermoresponsive Properties For Sustained Release Of Insulin To The Retina., Gauri P. Misra, Ravi S.J. Singh, Tomas S. Aleman, Samuel G. Jacobson, Thomas W. Gardner, Tao L. Lowe

College of Pharmacy Faculty Papers

The objective of this work is to develop subconjunctivally implantable, biodegradable hydrogels for sustained release of intact insulin to the retina to prevent and treat retinal neurovascular degeneration such as diabetic retinopathy. The hydrogels are synthesized by UV photopolymerization of N-isopropylacrylamide (NIPAAm) monomer and a dextran macromer containing multiple hydrolytically degradable oligolactate-(2-hydroxyetheyl methacrylate) units (Dex-lactateHEMA) in 25:75 (v:v) ethanol:water mixture solvent. Insulin is loaded into the hydrogels during the synthesis process with loading efficiency up to 98%. The hydrogels can release biologically active insulin in vitro for at least one week and the release kinetics can be modulated by varying …

Development Of A Mouse Monoclonal Antibody Cocktail For Post-Exposure Rabies Prophylaxis In Humans., Thomas Müller, Bernhard Dietzschold, Hildegund Ertl, Anthony R Fooks, Conrad Freuling, Christine Fehlner-Gardiner, Jeannette Kliemt, Francois X Meslin, Charles E Rupprecht, Noël Tordo, Alexander I Wanderler, Marie Paule Kieny

Department of Microbiology and Immunology Faculty Papers

As the demand for rabies post-exposure prophylaxis (PEP) treatments has increased exponentially in recent years, the limited supply of human and equine rabies immunoglobulin (HRIG and ERIG) has failed to provide the required passive immune component in PEP in countries where canine rabies is endemic. Replacement of HRIG and ERIG with a potentially cheaper and efficacious alternative biological for treatment of rabies in humans, therefore, remains a high priority. In this study, we set out to assess a mouse monoclonal antibody (MoMAb) cocktail with the ultimate goal to develop a product at the lowest possible cost that can be used …

Asymmetric Deactivation Of Hiv-1 Gp41 Following Fusion Inhibitor Binding., Kristen M Kahle, H Kirby Steger, Michael J Root

Department of Biochemistry and Molecular Biology Faculty Papers

Both equilibrium and nonequilibrium factors influence the efficacy of pharmaceutical agents that target intermediate states of biochemical reactions. We explored the intermediate state inhibition of gp41, part of the HIV-1 envelope glycoprotein complex (Env) that promotes viral entry through membrane fusion. This process involves a series of gp41 conformational changes coordinated by Env interactions with cellular CD4 and a chemokine receptor. In a kinetic window between CD4 binding and membrane fusion, the N- and C-terminal regions of the gp41 ectodomain become transiently susceptible to inhibitors that disrupt Env structural transitions. In this study, we sought to identify kinetic parameters that …

Traumatic Thoracic Asia A Examinations And Potential For Clinical Trials, James S. Harrop, Md, Mitchell G. Maltenfort, Phd, Fred H. Geisler, Md, Phd, William Coleman, Phd, Linda A.T. Jones, Pt, Ms, Edward Wirth, Md, Alexander Vaccaro, Md, Phd

Department of Neurosurgery Faculty Papers

Study Design: Retrospective review of prospective database

Objectives: To define the variability of neurologic examination and recovery after non-penetrating complete thoracic spinal cord injuries (ASIA A).

Background Data: Neurologic examinations after SCI can be difficult and inconsistent. Unlike cervical SCI patients, alterations in thoracic (below T1) complete SCI (ASIA A – based on the ASIA Impairment Scale [AIS]) patients’ exams are based only on sensory testing, thus changes in the neurological level (NL) are determined only by sensory changes.

Methods: A retrospective review of the placebo control patients in a multicenter prospective database utilized for the pharmacologic trial of Sygen. …

Airway Smooth Muscle As An Immunomodulatory Cell., Gautam Damera, Omar Tliba, Reynold A. Panettieri, Jr.

College of Pharmacy Faculty Papers

Although pivotal in regulating bronchomotor tone in asthma, airway smooth muscle (ASM) also modulates airway inflammation in asthma. ASM myocytes secrete or express a wide array of immunomodulatory mediators in response to extracellular stimuli, and in chronic severe asthma, increases in ASM mass may also render the airway irreversibly obstructed. Although the mechanisms by which ASM secretes cytokines and chemokines are shared with those regulating immune cells, there exist unique ASM signaling pathways that may provide novel therapeutic targets. This review provides an overview of our current understanding of the proliferative as well as synthetic properties of ASM.

Transcriptional Regulation Of Cytokine Function In Airway Smooth Muscle Cells., Deborah Clarke, Gautam Damera, Maria B. Sukkar, Omar Tliba

College of Pharmacy Faculty Papers

The immuno-modulatory properties of airway smooth muscle have become of increasing importance in our understanding of the mechanisms underlying chronic inflammation and structural remodeling of the airway wall in asthma and chronic obstructive pulmonary disease (COPD). ASM cells respond to many cytokines, growth factors and lipid mediators to produce a wide array of immuno-modulatory molecules which may in turn orchestrate and perpetuate the disease process in asthma and COPD. Despite numerous studies of the cellular effects of cytokines on cultured ASM, few have identified intracellular signaling pathways by which cytokines modulate or induce these cellular responses. In this review we …

Foxp3-Expressing T Regulatory Cells (T-Regs) Increase With The Severity Of Active Disease In Chronic Hepatitis C, Adam D. Toll, Md, John L. Farber, Md

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The hepatitis C virus (HCV) leads to chronic disease in 80% of those infected and is associated with a chronic inflammatory response that is mediated by both cytokine producing (CD4+) and cytotoxic T cells (CD8+). FoxP3-expressing, CD4+, CD25+T cells (T-regs) are a subset of T lymphocytes that inhibit immune responsiveness and thereby control immunological reactions. Whether FoxP3+ T regulatory cell-mediated suppression is a factor in HCV persistence and/or the course of chronic liver injury has not been defined. In order to assess the association between these T regulatory cells and the severity of chronic hepatitis C, we evaluated liver biopsies …

The Production Of Antibody By Invading B Cells Is Required For The Clearance Of Rabies Virus From The Central Nervous System., D Craig Hooper, Timothy W Phares, Marzena J Fabis, Anirban Roy

Department of Cancer Biology Faculty Papers

BACKGROUND: The pathogenesis of rabies is associated with the inability to deliver immune effectors across the blood-brain barrier and to clear virulent rabies virus from CNS tissues. However, the mechanisms that facilitate immune effector entry into CNS tissues are induced by infection with attenuated rabies virus.

METHODOLOGY/PRINCIPAL FINDINGS: Infection of normal mice with attenuated rabies virus but not immunization with killed virus can promote the clearance of pathogenic rabies virus from the CNS. T cell activity in B cell-deficient mice can control the replication of attenuated virus in the CNS, but viral mRNA persists. Low levels of passively administered rabies …

Establishing The Purity Of Mononuclear Cell Preparations Using Morphology And Flow Cytometry, Adam Holtz, Bs, Adam D. Toll, Md, Susan W. Burkholder, Md, Alicia M. Carlin, Ba, Linda F. Blumstein, Bs, Kathleen A. Schroeder, Bs, Eric M. Behling, Md, Tina B. Edmonston, Md

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Context: Simple tandem repeat loci are used to track bone marrow engraftment using mononuclear buffy coat cells and T-cells. Poor isolation purity of these subpopulations can result in lower analytical sensitivity of the bone marrow engraftment assay by diluting the cell population in question with other nucleated cells. Validation of the mononuclear cell preparation can be performed by flow cytometry or by counting cell populations on the slide. Conclusions: Our results show that the purity of the Histopaque-1077 mononuclear cell preparation is excellent and that morphology may be sufficient to validate the mononuclear cell isolation method if flow cytometry is …

Intracellular Bacteria Encode Inhibitory Snare-Like Proteins., Fabienne Paumet, Jordan Wesolowski, Alejandro Garcia-Diaz, Cedric Delevoye, Nathalie Aulner, Howard A Shuman, Agathe Subtil, James E Rothman

Department of Microbiology and Immunology Faculty Papers

Pathogens use diverse molecular machines to penetrate host cells and manipulate intracellular vesicular trafficking. Viruses employ glycoproteins, functionally and structurally similar to the SNARE proteins, to induce eukaryotic membrane fusion. Intracellular pathogens, on the other hand, need to block fusion of their infectious phagosomes with various endocytic compartments to escape from the degradative pathway. The molecular details concerning the mechanisms underlying this process are lacking. Using both an in vitro liposome fusion assay and a cellular assay, we showed that SNARE-like bacterial proteins block membrane fusion in eukaryotic cells by directly inhibiting SNARE-mediated membrane fusion. More specifically, we showed that …

N-Glycosylation Status Of E-Cadherin Controls Cytoskeletal Dynamics Through The Organization Of Distinct Β-Catenin- And Γ-Catenin-Containing Ajs., Basem T Jamal, Mihai Nita-Lazar, Zhennan Gao, Bakr Amin, Janice Walker, Maria A Kukuruzinska

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

N-glycosylation of E-cadherin has been shown to inhibit cell-cell adhesion. Specifically, our recent studies have provided evidence that the reduction of E-cadherin N-glycosylation promoted the recruitment of stabilizing components, vinculin and serine/threonine protein phosphatase 2A (PP2A), to adherens junctions (AJs) and enhanced the association of AJs with the actin cytoskeleton. Here, we examined the details of how N-glycosylation of E-cadherin affected the molecular organization of AJs and their cytoskeletal interactions. Using the hypoglycosylated E-cadherin variant, V13, we show that V13/β-catenin complexes preferentially interacted with PP2A and with the microtubule motor protein dynein. This correlated with dephosphorylation of the microtubule-associated protein …

The Otto Aufranc Award Identification Of A 4 Mb Region On Chromosome 17q21 Linked To Developmental Dysplasia Of The Hip In One 18-Member, Multigeneration Family, George Feldman, Chelsea Dalsey, Kasia Fertala, David Azimi, Paolo Fortina, Marcella Devoto, Maurizio Pacifici, Javad Parvizi

Department of Orthopaedic Surgery Faculty Papers

Developmental dysplasia of the hip (DDH) is a disabling condition of the hip that, depending on geography, can afflict between 20-80% of patients with end-stage arthritis of the hip. Despite its prevalence, the etiology of this disease remains unknown. DDH is a complex disorder with both environmental and genetic causes.. Based on the literature, the candidate genes for the disease are HOXB9, collagen type I α1, and DLX 3. The purpose of our study was to map and characterize the gene or genes responsible for this disorder by family linkage analysis. We recruited one 18-member, multigeneration affected family to provide …

Cd34 And Alpha-Smooth Muscle Actin Distinguish Cryptogenic Organizing Pneumonia From Secondary Bronchiolitis Obliterans-Organizing Pneumonia, Karen N. Wu, Md, Tajender S. Vasu, Md, John L. Farber, Md

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Secondary bronchiolitis obliterans-organizing pneumonia (BOOP) is a reaction to injury, forming granulation tissue with airspaces. Idiopathic cryptogenic organizing pneumonia (COP) and secondary BOOP are histologically similar. COP has been reported to show increased collagen in the granulation plugs and fewer myofibroblasts and capillaries. Using CD34 for capillaries and alpha-smooth muscle actin for myofibroblasts, we assessed these statins to differentiate COP from secondary BOOP.

The Elucidation Of Metabolic Pathways And Their Improvements Using Stable Optimization Of Large-Scale Kinetic Models Of Cellular Systems, Evgeni V. Nikolaev

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Metabolic engineering of cellular systems to maximize reaction fluxes or metabolite concentrations still presents a significant challenge by encountering unpredictable instabilities that can be caused by simultaneous or consecutive enhancements of many reaction steps. It can therefore be important to select carefully small subsets of key enzymes for their subsequent stable modification compatible with cell physiology. To address this important problem, we introduce a general mixed integer non-linear problem (MINLP) formulation to compute automatically which enzyme levels should be modulated and which enzyme regulatory structures should be altered to achieve the given optimization goal using non-linear kinetic models of relevant …

Detection Of Merkel Cell Carcinoma Polyomavirus In Mucosal Merkel Cell Carcinoma, Karen N. Wu, Md, Peter A. Mccue, Md, Zi-Xuan Wang, Phd, Agnieszka K. Witkiewicz, Md

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Case Report: A 61-year-old-woman with a past medical history significant for hypertension, bipolar disorder, obstructive sleep apnea and chronic obstructive pulmonary disease presented with diffusive lymphadenopathy suspicious for lymphoma. A lymph node in her right groin was biopsied by fine needle aspiration and showed atypical cells, but was not diagnostic. An excisional biopsy of the 2 x 2 cm lymph node demonstrated metastatic Merkel cell carcinoma (MCC). No skin lesions were detected. A CT scan revealed the presence of a large nasopharyngeal mass that following surgical removal was diagnosed as MCC. Treatment with etoposide and cisplatin and radiation were instituted. …

Inaugural Target Discovery World Congress 2009: Interactive Cardiovascular And Thoracic Surgery, Michael Holinstat, Ph.D.

Department of Medicine Faculty Papers

Dr. Michael Holinstat advocated a preferred therapeutic approach to treatment of platelet clot formation: to target signaling components downstream of receptor activation.

Intra-Tumor Heterogeneity Of Mlh1 Promoter Methylation Revealed By Deep Single Molecule Bisulfite Sequencing., Katherine E Varley, David G Mutch, Tina B Edmonston, Paul J Goodfellow, Robi D Mitra

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

A single tumor may contain cells with different somatic mutations. By characterizing this genetic heterogeneity within tumors, advances have been made in the prognosis, treatment and understanding of tumorigenesis. In contrast, the extent of epigenetic intra-tumor heterogeneity and how it influences tumor biology is under-explored. We have characterized epigenetic heterogeneity within individual tumors using next-generation sequencing. We used deep single molecule bisulfite sequencing and sample-specific DNA barcodes to determine the spectrum of MLH1 promoter methylation across an average of 1000 molecules in each of 33 individual samples in parallel, including endometrial cancer, matched blood and normal endometrium. This first glimpse, …

Effectiveness Of A Clinical Decision Support System To Identify Heparin Induced Thrombocytopenia., Jeffrey M. Riggio, Md, Msc, Mandelin K. Cooper, Pharmd, Benjamin E. Leiby, Phd, Jeanine M. Walenga, Phd, Geno J. Merli, Md, Jonathan E. Gottlieb, Md

Department of Medicine Faculty Papers

BACKGROUND: Subtle decreases in platelet count may impede timely recognition of heparin-induced thrombocytopenia (HIT), placing the patient at increased risk of thrombotic events.

OBJECTIVE: A clinical decision support system (CDSS) was developed to alert physicians using computerized provider order entry when a patient with an active order for heparin experienced platelet count decreases consistent with HIT.

METHODS: Comparisons for timeliness of HIT identification and treatment were evaluated for the year preceding and year following implementation of the CDSS in patients with laboratory confirmation of HIT.

RESULTS: During the intervention time period, the CDSS alert occurred 41,922 times identifying 2,036 patients …

R992c (P.R1192c) Substitution In Collagen Ii Alters The Structure Of Mutant Molecules And Induces The Unfolded Protein Response., Hye Jin Chung, Deborah A. Jensen, Katarzyna Gawron, Andrzej Steplewski, Andrzej Fertala

Department of Dermatology and Cutaneous Biology Faculty Papers

We investigated the molecular bases of spondyloepiphyseal dysplasia (SED) associated with the R992C (p.R1192C) substitution in collagen II. At the protein level, we analyzed the structure and integrity of mutant molecules, and at the cellular level, we specifically studied the effects of the presence of the R992C collagen II on the biological processes taking place in host cells. Our studies demonstrated that mutant collagen II molecules were characterized by altered electrophoretic mobility, relatively low thermostability, the presence of atypical disulfide bonds, and slow rates of secretion into the extracellular space. Analyses of cellular responses to the presence of the mutant …

Title: Student Readiness For Interprofessional Learning: Baseline And Midpoint In The Jefferson Health Mentor Program, Elena M. Umland, Cynthia A. Sanoski, Jon Veloski, Kevin Lyons, Carolyn Giordano, Christine Arenson, Molly Rose

College of Pharmacy Faculty Papers

Objectives: To measure pharmacy student readiness for interprofessional education (IPE) and compare the results to medical, nursing, occupational therapy (OT), and physical therapy (PT) student peers using the Readiness for Interprofessional Learning Scale (RIPLS).

Methods: First-year medical, nursing, OT, pharmacy, and PT students (n=544) participate in a 2-year longitudinal, interdisciplinary curriculum where they are assigned to a team including a Health Mentor (patient volunteer with chronic condition). Aims include understanding team roles and patient-centered care. All students complete the RIPLS at baseline and after completing years 1 and 2. RIPLS contains 3 subscales related to readiness for IPE: 1.)teamwork and …

Nerve Injection Of Viral Vectors Efficiently Transfers Transgenes Into Motor Neurons And Delivers Rnai Therapy Against Als., Rui Wu, Hongyan Wang, Xugang Xia, Hongxia Zhou, Chunyan Liu, Maria Castro, Zuoshang Xu

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

RNA interference (RNAi) mediates sequence-specific gene silencing, which can be harnessed to silencing disease-causing genes for therapy. Particularly suitable diseases are those caused by dominant, gain-of-function type of gene mutations. In these diseases, the mutant gene generates a mutant protein or RNA product, which possesses toxic properties that harm cells. By silencing the mutant gene, the toxicity can be lessened because the amount of the toxic product is lowered in cells. In this report, we tested RNAi therapy in a mouse model for amyotrophic lateral sclerosis (ALS), which causes motor neuron degeneration, paralysis, and death. We used a transgenic model …

Intravenous Inoculation Of A Bat-Associated Rabies Virus Causes Lethal Encephalopathy In Mice Through Invasion Of The Brain Via Neurosecretory Hypothalamic Fibers., Mirjam A R Preuss, Marie-Luise Faber, Gene S Tan, Michael Bette, Bernhard Dietzschold, Eberhard Weihe, Matthias J Schnell

Department of Microbiology and Immunology Faculty Papers

The majority of rabies virus (RV) infections are caused by bites or scratches from rabid carnivores or bats. Usually, RV utilizes the retrograde transport within the neuronal network to spread from the infection site to the central nervous system (CNS) where it replicates in neuronal somata and infects other neurons via trans-synaptic spread. We speculate that in addition to the neuronal transport of the virus, hematogenous spread from the site of infection directly to the brain after accidental spill over into the vascular system might represent an alternative way for RV to invade the CNS. So far, it is unknown …

Interaction With Lc8 Is Required For Pak1 Nuclear Import And Is Indispensable For Zebrafish Development., Christine M Lightcap, Gabor Kari, Luis E Arias-Romero, Jonathan Chernoff, Ulrich Rodeck, John C Williams

Department of Biochemistry and Molecular Biology Faculty Papers

Pak1 (p21 activated kinase 1) is a serine/threonine kinase implicated in regulation of cell motility and survival and in malignant transformation of mammary epithelial cells. In addition, the dynein light chain, LC8, has been described to cooperate with Pak1 in malignant transformation of breast cancer cells. Pak1 itself may aid breast cancer development by phosphorylating nuclear proteins, including estrogen receptor alpha. Recently, we showed that the LC8 binding site on Pak1 is adjacent to the nuclear localization sequence (NLS) required for Pak1 nuclear import. Here, we demonstrate that the LC8-Pak1 interaction is necessary for epidermal growth factor (EGF)-induced nuclear import …

Decorin Is A Novel Antagonistic Ligand Of The Met Receptor., Silvia Goldoni, Ashley Humphries, Alexander Nyström, Sampurna Sattar, Rick T Owens, David J Mcquillan, Keith Ireton, Renato V Iozzo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Decorin, a member of the small leucine-rich proteoglycan gene family, impedes tumor cell growth by down-regulating the epidermal growth factor receptor. Decorin has a complex binding repertoire, thus, we predicted that decorin would modulate the bioactivity of other tyrosine kinase receptors. We discovered that decorin binds directly and with high affinity (K(d) = approximately 1.5 nM) to Met, the receptor for hepatocyte growth factor (HGF). Binding of decorin to Met is efficiently displaced by HGF and less efficiently by internalin B, a bacterial Met ligand. Interaction of decorin with Met induces transient receptor activation, recruitment of the E3 ubiquitin ligase …