DOCSLIB.ORG

Eph Receptor Signaling and Ephrins

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Eph Receptor Signaling and Ephrins Downloaded from http://cshperspectives.cshlp.org/ on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Eph Receptor Signaling and Ephrins Erika M. Lisabeth1, Giulia Falivelli1,2, and Elena B. Pasquale1,3 1Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California 92037 2Department of Pharmacology, University of Bologna, Bologna 40100, Italy 3Department of Pathology, University of California San Diego, La Jolla, California 92093 Correspondence: [email protected] The Eph receptors are the largest of the RTK families. Like other RTKs, they transduce signals from the cell exterior to the interior through ligand-induced activation of their kinase domain. However, the Eph receptors also have distinctive features. Instead of binding soluble ligands, they generally mediate contact-dependent cell–cell communication by interacting with surface-associated ligands—the ephrins—on neighboring cells. Eph re- ceptor–ephrin complexes emanate bidirectional signals that affect both receptor- and ephrin-expressing cells. Intriguingly, ephrins can also attenuate signaling by Eph receptors coexpressed in the same cell. Additionally, Eph receptors can modulate cell behavior inde- pendently of ephrin binding and kinase activity. The Eph/ephrin system regulates many developmental processes and adult tissue homeostasis. Its abnormal function has been implicated in various diseases, including cancer. Thus, Eph receptors represent promising therapeutic targets. However, more research is needed to better understand the many aspects of their complex biology that remain mysterious. he Eph receptors have the prototypical RTK vent kinase activity. Furthermore, a variety of Ttopology, with a multidomain extracellular alternatively spliced forms identified for many region that includes the ephrin ligand-binding Eph receptors differ from the prototypical struc- domain, a single transmembrane segment, and a ture and have distinctive functions (Zisch and cytoplasmic region that contains the kinase do- Pasquale 1997; Pasquale 2010). main (Fig. 1). There are nine EphA receptors Both ephrin classes include a conserved Eph in the human genome, which promiscuously receptor-binding domain, which is connected bind five ephrin-A ligands and five EphB recep- to the plasma membrane by a linker segment tors, which promiscuously bind three ephrin- whose length can be affected by alternative splic- B ligands (Pasquale 2004, 2005). Additionally, ing (Fig. 1). The ephrin-As are attached to the EphA4 and EphB2 can also bind ephrins of a cell surface by a glycosylphosphatidylinositol different class. Two members of the family, (GPI) anchor, although they can also be released EphA10 and EphB6, have modifications in con- to activate EphA receptors at a distance (Bartley served regions of their kinase domains that pre- et al. 1994; Wykosky et al. 2008), whereas the Editors: Joseph Schlessinger and Mark A. Lemmon Additional Perspectives on Signaling by Receptor Tyrosine Kinases available at www.cshperspectives.org Copyright # 2013 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a009159 Cite this article as Cold Spring Harb Perspect Biol 2013;5:a009159 1 Downloaded from http://cshperspectives.cshlp.org/ on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press E.M. Lisabeth et al. Ephrin-B can be expressed in complementary gradients. Ephrin-A These situations likely reflect different signaling modalities with different biological outcomes. Eph receptors and ephrins engage in a mul- Ephrin binding titude of activities. They typically mediate con- Sushi tact-dependent communication between cells of the same or different types to control cell mor- EGF phology, adhesion, movement, proliferation, survival, and differentiation (Pasquale 2005). Fibronectin type III Through these activities, during development, the Eph/ephrin system plays a role in the spatial Juxtamembrane organization of different cell populations, ax- Kinase on guidance, formation of synaptic connections between neurons, and blood vessel remodeling. SAM In the adult, the Eph/ephrin system regulates PDZ binding remodeling of synapses, epithelial differentia- tion and integrity, bone remodeling, immune EphA EphB function, insulin secretion, and stem cell self- Figure 1. Domain structure of Eph receptors and renewal (Pasquale 2008; Genander and Frisen ephrins. 2010). In addition, Eph receptors and ephrins are often up-regulated in injured tissues, where they inhibit some regenerative processes but ephrin-Bs contain a transmembrane segment promote angiogenesis, as well as in cancer cells, and a short cytoplasmic region. Ephrin-A3 and where they seem to be able to both promote and ephrin-B3 also bind heparan sulfate proteogly- suppress tumorigenicity (Du et al. 2007; Pas- cans through an interaction that involves their quale 2008, 2010). extracellular linker region and that, at least in Herewe provide an overview of Eph receptor the case of ephrin-A3, potentiates EphA recep- and ephrin signaling mechanisms and biologi- tor activation and signaling (Irie et al. 2008; cal effects, with an emphasis on recent findings. Holen et al. 2011). More detailed information on specific aspects of The Eph receptor family has greatly expand- Eph receptor/ephrin biology and downstream ed during evolution, and includes almost one signaling networks can be found in other recent fourth of the 58 human RTKs (Schlessinger reviews (Pasquale 2005, 2008, 2010; Arvanitis and Lemmon 2013). A large number of Eph re- and Davy 2008; Lackmann and Boyd 2008; Klein ceptors and ephrins may be required to achieve 2009; Genander and Frisen 2010). and maintain the sophisticated tissue organi- zation of higher organisms. Indeed, many are EPH RECEPTOR FORWARD SIGNALING highly expressed in the most complex organ, the brain, particularly during the establishment “Forward” signaling corresponds to the proto- of its complex architecture and intricate wir- typical RTK mode of signaling, which is trig- ing of neuronal connections (Yamaguchi and gered by ligand binding and involves activation Pasquale 2004). Besides the brain, Eph recep- of the kinase domain. However, the activation tors and ephrins are also present in most— mechanisms of Eph receptors have unique fea- if not all—other tissues, often in acombinatorial tures as compared to other RTK families (Barton manner and with dynamically changing ex- et al. 2013). Binding between Eph receptors pression patterns (Pasquale 2005). In some re- and ephrins on juxtaposed cell surfaces leads gions, Eph receptors and ephrins are both coex- to oligomerization through not only Eph recep- pressed in the same cells, in others they have tor–ephrin interfaces but also receptor–recep- mutually exclusive expression patterns or they tor cis interfaces located in multiple domains 2 Cite this article as Cold Spring Harb Perspect Biol 2013;5:a009159 Downloaded from http://cshperspectives.cshlp.org/ on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Eph Receptor Signaling and Ephrins PDZ Src SH2 P P P Ephrin-A * * coreceptor * * * * * P P SH2 P P P P ATP ATP ATP P GAP GEF P Phosphatase P * PDZ Figure 2. Eph receptor clustering and bidirectional signaling. SH2 and PDZ indicate proteins containing these domains. All types of signaling proteins shown can associate with both EphA and EphB receptors. Asterisks indicate receptor–receptor interactions favoring clustering; yellow circles indicate tyrosine phosphorylation and the orange circle indicates serine phosphorylation. (Fig. 2) (Himanen et al. 2010; Seiradake et al. for maximal activity (Binns et al. 2000; Singla 2010). In fact, Eph receptor clusters induced by et al. 2011). There are also differences in the ephrin binding can enlarge to incorporate Eph kinase domains within the Eph receptor family. receptors that are not bound to ephrins For example, the “gatekeeper” residue in the (Wimmer-Kleikamp et al. 2004). The cellular hinge region between the kinase domain lobes, context can also affect Eph receptor clustering which controls access to a hydrophobic pocket ability, which depends on association with the adjacent to the ATP-binding site, is a threonine actin cytoskeleton (Salaita and Groves 2010). in most Eph receptors but a valine in EphA6 Given the promiscuity of Eph receptor–ephrin and an isoleucine in EphA7. Hence, EphA6 and interactions, and also receptor–receptor cis in- EphA7 likely differ from the other Eph recep- teractions, the clusters can include Eph recep- tors in their sensitivity to kinase inhibitors and tors of both A and B classes (Janes et al. 2011). possibly substrate specificity (Skaggs et al. 2006; The proximity of clustered Eph receptor Zhang et al. 2009a). molecules leads to trans-phosphorylation. Phos- The Eph receptors modulate many of the phorylation of two conserved tyrosines in the same networks of adaptor and effector proteins juxtamembrane domain relieves inhibitory in- that also function downstream of other RTK tramolecular interactions with the kinase do- families (Wagner et al. 2013). Various tyrosine main, enabling efficient kinase activity (Binns autophosphorylation sites in activated Eph re- et al. 2000; Zisch et al. 2000; Wybenga-Groot ceptors—including the two regulatory juxta- et al. 2001). Phosphorylation of the conserved membrane sites—enable recruitment of down- tyrosine in the activation loop appears to be less stream signaling proteins that contain SH2 critical for Eph receptor activation than it is for domains, including nonreceptor
Load more

Recommended publications
  • Epha Receptors and Ephrin-A Ligands Are Upregulated by Monocytic
    Mukai et al. BMC Cell Biology (2017) 18:28 DOI 10.1186/s12860-017-0144-x RESEARCHARTICLE Open Access EphA receptors and ephrin-A ligands are upregulated by monocytic differentiation/ maturation and promote cell adhesion and protrusion formation in HL60 monocytes Midori Mukai, Norihiko Suruga, Noritaka Saeki and Kazushige Ogawa* Abstract Background: Eph signaling is known to induce contrasting cell behaviors such as promoting and inhibiting cell adhesion/ spreading by altering F-actin organization and influencing integrin activities. We have previously demonstrated that EphA2 stimulation by ephrin-A1 promotes cell adhesion through interaction with integrins and integrin ligands in two monocyte/ macrophage cell lines. Although mature mononuclear leukocytes express several members of the EphA/ephrin-A subclass, their expression has not been examined in monocytes undergoing during differentiation and maturation. Results: Using RT-PCR, we have shown that EphA2, ephrin-A1, and ephrin-A2 expression was upregulated in murine bone marrow mononuclear cells during monocyte maturation. Moreover, EphA2 and EphA4 expression was induced, and ephrin-A4 expression was upregulated, in a human promyelocytic leukemia cell line, HL60, along with monocyte differentiation toward the classical CD14++CD16− monocyte subset. Using RT-PCR and flow cytometry, we have also shown that expression levels of αL, αM, αX, and β2 integrin subunits were upregulated in HL60 cells along with monocyte differentiation while those of α4, α5, α6, and β1 subunits were unchanged. Using a cell attachment stripe assay, we have shown that stimulation by EphA as well as ephrin-A, likely promoted adhesion to an integrin ligand- coated surface in HL60 monocytes. Moreover, EphA and ephrin-A stimulation likely promoted the formation of protrusions in HL60 monocytes.
    [Show full text]
  • Supplemental Material 1
    Supplemental Fig. 1 12 1mg/ml A1AT p<0.001 10 8 p=0.004 6 p=0.029 (fold change) 4 mRNA ofmRNA angptl4 at h 1 2 0 Control Prolastin Aralast A1AT Sigma Supplemental Figure 1. Adherent PBMCs were incubated with 1 mg/ml A1AT from different sources (Prolastin, Grifols; Aralast, Baxter; or Sigma Aldrich) for 1h and mRNA levels of angplt4 were determined by RT-PCR. Bars represent the mean ± SD of four experiments. Supplemental Fig. 2 12 8 h p=0.005 10 8 6 mRNA angplt4 mRNA change Fold 4 2 0 Control A1AT 0.5 mg/ml Supplemental Figure 2. HMVEC-L were incubated with 0.5 mg/ml A1AT (Calbiochem) for 8 h and mRNA levels of angptl4 were determined by RT-PCR. Bars represent the mean ± SEM of three experiments. Supplemental Table I. Influence of A1AT (1 mg/ml, 8 h) on expression of angiogenesis genesa in HMVEC-L Unigene Symbol Description Gname fold changeb Hs.525622 AKT1 V-akt murine thymoma viral AKT/MGC99656/PKB/PKB- 0,94 0,14 oncogene homolog 1 ALPHA/PRKBA/RAC/RAC- ALPHA Hs.369675 ANGPT1 Angiopoietin 1 AGP1/AGPT/ANG1 3,61 5,11 Hs.583870 ANGPT2 Angiopoietin 2 AGPT2/ANG2 0,98 0,01 Hs.209153 ANGPTL3 Angiopoietin-like 3 ANGPT5/FHBL2 1,10 0,59 Hs.9613 ANGPTL4 Angiopoietin-like 4 ANGPTL2/ARP4/FIAF/HFAR 5,79 1,66 P/NL2/PGAR/pp1158 Hs.1239 ANPEP Alanyl (membrane) APN/CD13/GP150/LAP1/P150 1,03 0,01 aminopeptidase /PEPN Hs.194654 BAI1 Brain-specific angiogenesis FLJ41988/GDAIF 0,89 0,26 inhibitor 1 Hs.54460 CCL11 Chemokine (C-C motif) ligand 11 MGC22554/SCYA11 1,04 0,15 Hs.303649 CCL2 Chemokine (C-C motif) ligand 2 GDCF- 1,09 0,14 2/HC11/HSMCR30/MCAF/M CP-
    [Show full text]
  • Detection of Pro Angiogenic and Inflammatory Biomarkers in Patients With
    www.nature.com/scientificreports OPEN Detection of pro angiogenic and infammatory biomarkers in patients with CKD Diana Jalal1,2,3*, Bridget Sanford4, Brandon Renner5, Patrick Ten Eyck6, Jennifer Laskowski5, James Cooper5, Mingyao Sun1, Yousef Zakharia7, Douglas Spitz7,9, Ayotunde Dokun8, Massimo Attanasio1, Kenneth Jones10 & Joshua M. Thurman5 Cardiovascular disease (CVD) is the most common cause of death in patients with native and post-transplant chronic kidney disease (CKD). To identify new biomarkers of vascular injury and infammation, we analyzed the proteome of plasma and circulating extracellular vesicles (EVs) in native and post-transplant CKD patients utilizing an aptamer-based assay. Proteins of angiogenesis were signifcantly higher in native and post-transplant CKD patients versus healthy controls. Ingenuity pathway analysis (IPA) indicated Ephrin receptor signaling, serine biosynthesis, and transforming growth factor-β as the top pathways activated in both CKD groups. Pro-infammatory proteins were signifcantly higher only in the EVs of native CKD patients. IPA indicated acute phase response signaling, insulin-like growth factor-1, tumor necrosis factor-α, and interleukin-6 pathway activation. These data indicate that pathways of angiogenesis and infammation are activated in CKD patients’ plasma and EVs, respectively. The pathways common in both native and post-transplant CKD may signal similar mechanisms of CVD. Approximately one in 10 individuals has chronic kidney disease (CKD) rendering CKD one of the most common diseases worldwide1. CKD is associated with a high burden of morbidity in the form of end stage kidney disease (ESKD) requiring dialysis or transplantation 2. Furthermore, patients with CKD are at signifcantly increased risk of death from cardiovascular disease (CVD)3,4.
    [Show full text]
  • Functional Analysis of Somatic Mutations Affecting Receptor Tyrosine Kinase Family in Metastatic Colorectal Cancer
    Author Manuscript Published OnlineFirst on March 29, 2019; DOI: 10.1158/1535-7163.MCT-18-0582 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Functional analysis of somatic mutations affecting receptor tyrosine kinase family in metastatic colorectal cancer Leslie Duplaquet1, Martin Figeac2, Frédéric Leprêtre2, Charline Frandemiche3,4, Céline Villenet2, Shéhérazade Sebda2, Nasrin Sarafan-Vasseur5, Mélanie Bénozène1, Audrey Vinchent1, Gautier Goormachtigh1, Laurence Wicquart6, Nathalie Rousseau3, Ludivine Beaussire5, Stéphanie Truant7, Pierre Michel8, Jean-Christophe Sabourin9, Françoise Galateau-Sallé10, Marie-Christine Copin1,6, Gérard Zalcman11, Yvan De Launoit1, Véronique Fafeur1 and David Tulasne1 1 Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T – Mechanisms of Tumorigenesis and Target Therapies, F-59000 Lille, France. 2 Univ. Lille, Plateau de génomique fonctionnelle et structurale, CHU Lille, F-59000 Lille, France 3 TCBN - Tumorothèque Caen Basse-Normandie, F-14000 Caen, France. 4 Réseau Régional de Cancérologie – OncoBasseNormandie – F14000 Caen – France. 5 Normandie Univ, UNIROUEN, Inserm U1245, IRON group, Rouen University Hospital, Normandy Centre for Genomic and Personalized Medicine, F-76000 Rouen, France. 6 Tumorothèque du C2RC de Lille, F-59037 Lille, France. 7 Department of Digestive Surgery and Transplantation, CHU Lille, Univ Lille, 2 Avenue Oscar Lambret, 59037, Lille Cedex, France. 8 Department of hepato-gastroenterology, Rouen University Hospital, Normandie Univ, UNIROUEN, Inserm U1245, IRON group, F-76000 Rouen, France. 9 Department of Pathology, Normandy University, INSERM 1245, Rouen University Hospital, F 76 000 Rouen, France. 10 Department of Pathology, MESOPATH-MESOBANK, Centre León Bérard, Lyon, France. 11 Thoracic Oncology Department, CIC1425/CLIP2 Paris-Nord, Hôpital Bichat-Claude Bernard, Paris, France.
    [Show full text]
  • Ephrin-A Binding and Epha Receptor Expression Delineate the Matrix Compartment of the Striatum
    The Journal of Neuroscience, June 15, 1999, 19(12):4962–4971 Ephrin-A Binding and EphA Receptor Expression Delineate the Matrix Compartment of the Striatum L. Scott Janis, Robert M. Cassidy, and Lawrence F. Kromer Department of Cell Biology and Interdisciplinary Program in Neuroscience, Georgetown University Medical Center, Washington, DC 20007 The striatum integrates limbic and neocortical inputs to regulate matrix neurons. In situ hybridization for EphA RTKs reveals that sensorimotor and psychomotor behaviors. This function is de- the two different ligand binding patterns strictly match pendent on the segregation of striatal projection neurons into the mRNA expression patterns of EphA4 and EphA7. anatomical and functional components, such as the striosome Ligand–receptor binding assays indicate that ephrin-A1 and and matrix compartments. In the present study the association ephrin-A4 selectively bind EphA4 but not EphA7 in the lysates of ephrin-A cell surface ligands and EphA receptor tyrosine of striatal tissue. Conversely, ephrin-A2, ephrin-A3, and kinases (RTKs) with the organization of these compartments ephrin-A5 bind EphA7 but not EphA4. These observations im- was determined in postnatal rats. Ephrin-A1 and ephrin-A4 plicate selective interactions between ephrin-A molecules and selectively bind to EphA receptors on neurons restricted to the EphA RTKs as potential mechanisms for regulating the com- matrix compartment. Binding is absent from the striosomes, partmental organization of the striatum. which were identified by m-opioid
    [Show full text]
  • Supplementary Table 1. in Vitro Side Effect Profiling Study for LDN/OSU-0212320. Neurotransmitter Related Steroids
    Supplementary Table 1. In vitro side effect profiling study for LDN/OSU-0212320. Percent Inhibition Receptor 10 µM Neurotransmitter Related Adenosine, Non-selective 7.29% Adrenergic, Alpha 1, Non-selective 24.98% Adrenergic, Alpha 2, Non-selective 27.18% Adrenergic, Beta, Non-selective -20.94% Dopamine Transporter 8.69% Dopamine, D1 (h) 8.48% Dopamine, D2s (h) 4.06% GABA A, Agonist Site -16.15% GABA A, BDZ, alpha 1 site 12.73% GABA-B 13.60% Glutamate, AMPA Site (Ionotropic) 12.06% Glutamate, Kainate Site (Ionotropic) -1.03% Glutamate, NMDA Agonist Site (Ionotropic) 0.12% Glutamate, NMDA, Glycine (Stry-insens Site) 9.84% (Ionotropic) Glycine, Strychnine-sensitive 0.99% Histamine, H1 -5.54% Histamine, H2 16.54% Histamine, H3 4.80% Melatonin, Non-selective -5.54% Muscarinic, M1 (hr) -1.88% Muscarinic, M2 (h) 0.82% Muscarinic, Non-selective, Central 29.04% Muscarinic, Non-selective, Peripheral 0.29% Nicotinic, Neuronal (-BnTx insensitive) 7.85% Norepinephrine Transporter 2.87% Opioid, Non-selective -0.09% Opioid, Orphanin, ORL1 (h) 11.55% Serotonin Transporter -3.02% Serotonin, Non-selective 26.33% Sigma, Non-Selective 10.19% Steroids Estrogen 11.16% 1 Percent Inhibition Receptor 10 µM Testosterone (cytosolic) (h) 12.50% Ion Channels Calcium Channel, Type L (Dihydropyridine Site) 43.18% Calcium Channel, Type N 4.15% Potassium Channel, ATP-Sensitive -4.05% Potassium Channel, Ca2+ Act., VI 17.80% Potassium Channel, I(Kr) (hERG) (h) -6.44% Sodium, Site 2 -0.39% Second Messengers Nitric Oxide, NOS (Neuronal-Binding) -17.09% Prostaglandins Leukotriene,
    [Show full text]
  • Synchronous Overexpression of Epidermal Growth Factor Receptor and HER2-Neu Protein Is a Predictor of Poor Outcome in Patients with Stage I Non-Small Cell Lung Cancer
    136 Vol. 10, 136–143, January 1, 2004 Clinical Cancer Research Synchronous Overexpression of Epidermal Growth Factor Receptor and HER2-neu Protein Is a Predictor of Poor Outcome in Patients with Stage I Non-Small Cell Lung Cancer ؍ Amir Onn,1,2 Arlene M. Correa,3 nocarcinomas than in squamous cell carcinomas (P Michael Gilcrease,4 Takeshi Isobe,2 0.035). Synchronous overexpression of EGFR and HER2- 1 2 neu was found in 11 tumors (9.9%). Patients with these ؍ ,Erminia Massarelli, Corazon D. Bucana 2,5 1 tumors had a significantly shorter time to recurrence (P ؍ Michael S. O’Reilly, Waun K. Hong, 0.006) and a trend toward shorter overall survival (P 2 3 Isaiah J. Fidler, Joe B. Putnam, and 0.093). Phosphorylated EGFR and transforming growth fac- Roy S. Herbst1,2 tor ␣ were detected but were not related to prognosis. Departments of 1Thoracic/Head and Neck Medical Oncology, 2Cancer Conclusions: Synchronous overexpression of EGFR Biology, 3Thoracic and Cardiovascular Surgery, 4Pathology, and and HER2-neu at the protein level predicts increased recur- 5 Radiation Oncology, The University of Texas M. D. Anderson rence risk and may predict decreased survival in patients Cancer Center, Houston, Texas with stage I NSCLC. This suggests that important interac- tions take place among the different members of the ErbB ABSTRACT family during tumor development and suggests a method for choosing targeted therapy. A prospective study is planned. Purpose: Despite maximal therapy, surgically treated patients with stage I non-small cell lung cancer (NSCLC) are at risk for developing metastatic disease. Histopathologic INTRODUCTION findings cannot adequately predict disease progression, so The overall 5-year survival rate in patients with lung cancer there is a need to identify molecular factors that serve this is Ͻ15% (1).
    [Show full text]
  • Targeting the Function of the HER2 Oncogene in Human Cancer Therapeutics
    Oncogene (2007) 26, 6577–6592 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc REVIEW Targeting the function of the HER2 oncogene in human cancer therapeutics MM Moasser Department of Medicine, Comprehensive Cancer Center, University of California, San Francisco, CA, USA The year 2007 marks exactly two decades since human HER3 (erbB3) and HER4 (erbB4). The importance of epidermal growth factor receptor-2 (HER2) was func- HER2 in cancer was realized in the early 1980s when a tionally implicated in the pathogenesis of human breast mutationally activated form of its rodent homolog neu cancer (Slamon et al., 1987). This finding established the was identified in a search for oncogenes in a carcinogen- HER2 oncogene hypothesis for the development of some induced rat tumorigenesis model(Shih et al., 1981). Its human cancers. An abundance of experimental evidence human homologue, HER2 was simultaneously cloned compiled over the past two decades now solidly supports and found to be amplified in a breast cancer cell line the HER2 oncogene hypothesis. A direct consequence (King et al., 1985). The relevance of HER2 to human of this hypothesis was the promise that inhibitors of cancer was established when it was discovered that oncogenic HER2 would be highly effective treatments for approximately 25–30% of breast cancers have amplifi- HER2-driven cancers. This treatment hypothesis has led cation and overexpression of HER2 and these cancers to the development and widespread use of anti-HER2 have worse biologic behavior and prognosis (Slamon antibodies (trastuzumab) in clinical management resulting et al., 1989).
    [Show full text]
  • Ephrin-A2 Reverse Signaling Negatively Regulates Neural Progenitor Proliferation and Neurogenesis
    Downloaded from genesdev.cshlp.org on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press Ephrin-A2 reverse signaling negatively regulates neural progenitor proliferation and neurogenesis Johan Holmberg,1 Annika Armulik,1 Kirsten-André Senti,1,3 Karin Edoff,1 Kirsty Spalding,1 Stefan Momma,1 Rob Cassidy,1 John G. Flanagan,2 and Jonas Frisén1,4 1Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institute, SE-171 77 Stockholm, Sweden; 2Department of Cell Biology and Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115, USA The number of cells in an organ is regulated by mitogens and trophic factors that impinge on intrinsic determinants of proliferation and apoptosis. We here report the identification of an additional mechanism to control cell number in the brain: EphA7 induces ephrin-A2 reverse signaling, which negatively regulates neural progenitor cell proliferation. Cells in the neural stem cell niche in the adult brain proliferate more and have a shorter cell cycle in mice lacking ephrin-A2. The increased progenitor proliferation is accompanied by a higher number of cells in the olfactory bulb. Disrupting the interaction between ephrin-A2 and EphA7 in the adult brain of wild-type mice disinhibits proliferation and results in increased neurogenesis. The identification of ephrin-A2 and EphA7 as negative regulators of progenitor cell proliferation reveals a novel mechanism to control cell numbers in the brain. [Keywords: SVZ; adult; neuronal progenitors; proliferation; ephrins; reverse signaling] Supplemental material is available at http://www.genesdev.org. Received October 1, 2004; revised version accepted December 16, 2004. Most neurons are generated before birth and neurogen- ing proliferation and neurogenesis within the stem cell esis in the adult brain is limited to a few regions.
    [Show full text]
  • Systems-Level Analysis of Erbb4 Signaling in Breast Cancer: a Laboratory to Clinical Perspective
    Subject Review Systems-Level Analysis of ErbB4 Signaling in Breast Cancer: A Laboratory to Clinical Perspective Chih-Pin Chuu,1 Rou-Yu Chen,3 John L. Barkinge,1 Mark F. Ciaccio,1,2 and Richard B. Jones1 1The Ben May Department for Cancer Research and The Institute for Genomics and Systems Biology and 2The Committee on Cell Physiology, Gordon Center for Integrative Science, The University of Chicago; and 3Division of Immunotherapy, Department of Medicine, FeinbergSchool of Medicine, Northwestern University, Chicago, Illinois Abstract account the pregnancy history, lactation status, and Although expression of the ErbB4 receptor tyrosine hormone supplementation or ablation history of the kinase in breast cancer is generally regarded as a marker patient from whom the tumor or tumor cells are derived. for favorable patient prognosis, controversial (Mol Cancer Res 2008;6(6):885–91) exceptions have been reported. Alternative splicing of ErbB4 pre-mRNAs results in the expression of distinct Introduction receptor isoforms with differential susceptibility to Four receptors comprise the ErbB receptor tyrosine kinase enzymatic cleavage and different downstream signaling family: ErbB1 (epidermal growth factor receptor, HER1, c-erb- protein recruitment potential that could affect tumor B1), ErbB2 (HER2, neu, c-erb-B2), ErbB3 (HER3, c-erb-B3), progression in different ways. ErbB4 protein expression and ErbB4 (HER4, c-erb-B4). Whereas ErbB1 and ErbB2 are from nontransfected cells is generally low compared frequently overexpressed in breast cancer and correlate with a with ErbB1 in most cell lines, and much of our poor prognosis, ErbB4 expression in breast cancers actually knowledge of the role of ErbB4 in breast cancer is correlates with a favorable prognosis.
    [Show full text]
  • Rabbit Anti-Ephrin-A1 Rabbit Anti-Ephrin-A1
    Qty: 100 µg/400 µl Rabbit anti-ephrin-A1 Catalog No. 34-3300 Lot No. See product label Rabbit anti-ephrin-A1 FORM This polyclonal antibody is supplied as a 400 µl aliquot at a concentration of 0.25 mg/ml in phosphate buffered saline (pH 7.4) containing 0.1% sodium azide. The antibody is epitope-affinity-purified from rabbit antiserum. PAD: ZMD.39 IMMUNOGEN Synthetic peptide derived from the C-terminal end of mouse ephrin-A1 protein. SPECIFICITY This antibody is specific for the ephrin-A1 protein. REACTIVITY Reactivity is confirmed with a chimeric protein consisting of the extracellular domain of mouse ephrin-A1 and the Fc region of human IgG1. Cross-reactivity with human ephrin-A1 is confirmed with IHC experiments on human tissue sections and this reactivity was expected because of the 85% shared amino acid identity in the extracellular domain. Sample Western Immunoprecipitation Immunohistochemistry Blotting (FFPE) Mouse +++ +++ NT Human NT NT ++ (Excellent +++, Good++, Poor +, No reactivity 0, Not tested NT) USAGE Working concentrations for specific applications should be determined by the investigator. Appropriate concentrations will be affected by several factors, including secondary antibody affinity, antigen concentration, sensitivity of detection method, temperature and length of incubations, etc. The suitability of this antibody for applications other than those listed below has not been determined. The following concentration ranges are recommended starting points for this product. Western Blotting: 1-5 µg/mL Immunoprecipitation: 5-10 µg/ IP reaction Immunohistochemistry: 4-10 µg/mL Please note that immunohistochemical assays were optimized on formalin-fixed, paraffin-embedded tissue sections and Heat Induced Epitope Retrieval (HIER) with EDTA, pH 8.0 was required for optimal staining.
    [Show full text]
  • Beyond Traditional Morphological Characterization of Lung
    Cancers 2020 S1 of S15 Beyond Traditional Morphological Characterization of Lung Neuroendocrine Neoplasms: In Silico Study of Next-Generation Sequencing Mutations Analysis across the Four World Health Organization Defined Groups Giovanni Centonze, Davide Biganzoli, Natalie Prinzi, Sara Pusceddu, Alessandro Mangogna, Elena Tamborini, Federica Perrone, Adele Busico, Vincenzo Lagano, Laura Cattaneo, Gabriella Sozzi, Luca Roz, Elia Biganzoli and Massimo Milione Table S1. Genes Frequently mutated in Typical Carcinoids (TCs). Mutation Original Entrez Gene Gene Rate % eukaryotic translation initiation factor 1A X-linked [Source: HGNC 4.84 EIF1AX 1964 EIF1AX Symbol; Acc: HGNC: 3250] AT-rich interaction domain 1A [Source: HGNC Symbol;Acc: HGNC: 4.71 ARID1A 8289 ARID1A 11110] LDL receptor related protein 1B [Source: HGNC Symbol; Acc: 4.35 LRP1B 53353 LRP1B HGNC: 6693] 3.53 NF1 4763 NF1 neurofibromin 1 [Source: HGNC Symbol;Acc: HGNC: 7765] DS cell adhesion molecule like 1 [Source: HGNC Symbol; Acc: 2.90 DSCAML1 57453 DSCAML1 HGNC: 14656] 2.90 DST 667 DST dystonin [Source: HGNC Symbol;Acc: HGNC: 1090] FA complementation group D2 [Source: HGNC Symbol; Acc: 2.90 FANCD2 2177 FANCD2 HGNC: 3585] piccolo presynaptic cytomatrix protein [Source: HGNC Symbol; Acc: 2.90 PCLO 27445 PCLO HGNC: 13406] erb-b2 receptor tyrosine kinase 2 [Source: HGNC Symbol; Acc: 2.44 ERBB2 2064 ERBB2 HGNC: 3430] BRCA1 associated protein 1 [Source: HGNC Symbol; Acc: HGNC: 2.35 BAP1 8314 BAP1 950] capicua transcriptional repressor [Source: HGNC Symbol; Acc: 2.35 CIC 23152 CIC HGNC:
    [Show full text]