Role of an adaptor protein human germinal center-associated lymphoma (HGAL) in cell signaling and lymphomagenesis

Human germinal center (GC)-associated lymphoma (HGAL) is a multi-domain adaptor protein expressed in GC B lymphocytes, T follicular helper (Tfh) cells and lymphomas derived from these cells. HGAL expression is an independent predictor of longer survival of diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin’s lymphoma (HL) patients. HGAL regulates B cell receptor (BCR) signaling and immunological synapse formation by binding to either the downstream effectors [e.g., spleen tyrosine kinase (Syk)] or other signaling regulators [e.g., growth factor receptor-bound protein 2 (Grb2)]. HGAL regulates the cytoskeleton that reshapes B cell morphology during BCR signaling and cell motility by at least two molecular mechanisms: enhanced Ras homolog gene family member A (RhoA) signaling and inhibition of myosin-actin translocation. These effects on the cytoskeleton decrease lymphoma dissemination in animal models and contribute to decreased lymphoma dissemination in patients. The latter may contribute to the association of HGAL protein expression with longer survival of patients with DLBCL and HL tumors. The ability to regulate multiple and distinct functions simultaneously in B cells implies that the HGAL protein level is tightly regulated. It was demonstrated that HGAL can be regulated by PR/SET domain 1 (PRDM1)/B lymphocyte-induced maturation protein-1 (BLIMP1) and interleukin-4 (IL-4) at the transcription level, by microRNA-155 (miR-155) at the post-transcriptional level, and by F-box protein 10 (FBXO10) at the post-translational level. Constitutive enforced expression of HGAL at physiological levels leads to lymphoid hyperplasia and DLBCL in mice. Future studies need to focus on identifying HGAL interactome, dissecting its interaction network, and understanding HGAL spatiotemporal signaling in live cells in physiological conditions. Further, the recent demonstration of HGAL expression in Tfh cells requires the determination of its function in these cells. These studies will contribute to new insights into the biology of these cellular subsets and how immune dysregulation contributes to lymphomagenesis.

[1]  I. Lossos,et al.  Human Germinal Center–associated Lymphoma (HGAL) Is a Reliable Marker of Normal and Neoplastic Follicular Helper T Cells Including Angioimmunoblastic T-Cell Lymphoma , 2021, The American journal of surgical pathology.

[2]  C. Pairojkul,et al.  Adaptor protein XB130 regulates the aggressiveness of cholangiocarcinoma , 2021, PloS one.

[3]  T. Matsuda,et al.  Signal-transducing adaptor protein-1 and -2 in hematopoiesis and diseases. , 2021, Experimental hematology.

[4]  I. Lossos,et al.  HGAL inhibits lymphoma dissemination by interacting with multiple cytoskeletal proteins , 2021, Blood advances.

[5]  J. Trejo,et al.  The α-arrestin ARRDC3 is an Emerging Multifunctional Adaptor Protein in Cancer. , 2021, Antioxidants & redox signaling.

[6]  M. Tomayko,et al.  Memory B cells and plasma cells: The differentiative continuum of humoral immunity , 2021, Immunological reviews.

[7]  R. Brink,et al.  The unique biology of germinal center B cells. , 2021, Immunity.

[8]  Azhar Ali,et al.  Protein Lipidation by Palmitoylation and Myristoylation in Cancer , 2021, Frontiers in Cell and Developmental Biology.

[9]  James E. Tomkins,et al.  Advances in protein-protein interaction network analysis for Parkinson's disease , 2021, Neurobiology of Disease.

[10]  L. Shapiro,et al.  A localized adaptor protein performs distinct functions at the Caulobacter cell poles , 2021, Proceedings of the National Academy of Sciences.

[11]  Jiang Ren,et al.  Protein N-myristoylation: functions and mechanisms in control of innate immunity , 2021, Cellular & Molecular Immunology.

[12]  B. Thompson Par‐3 family proteins in cell polarity & adhesion , 2021, The FEBS journal.

[13]  J. Hildebrand,et al.  Location, location, location: A compartmentalized view of TNF-induced necroptotic signaling , 2021, Science Signaling.

[14]  R. Papa,et al.  Actin Remodeling Defects Leading to Autoinflammation and Immune Dysregulation , 2021, Frontiers in Immunology.

[15]  M. Potente,et al.  Arterialization requires the timely suppression of cell growth , 2020, Nature.

[16]  M. Shlomchik,et al.  Germinal Center and Extrafollicular B Cell Responses in Vaccination, Immunity, and Autoimmunity. , 2020, Immunity.

[17]  Xiuling Zhi,et al.  Protein palmitoylation and its pathophysiological relevance , 2020, Journal of cellular physiology.

[18]  I. Lossos,et al.  Conditional expression of HGAL leads to the development of diffuse large B-cell lymphoma in mice. , 2020, Blood.

[19]  T. Kuijpers,et al.  When Actin is Not Actin’ Like It Should: A New Category of Distinct Primary Immunodeficiency Disorders , 2020, Journal of Innate Immunity.

[20]  X. Bian,et al.  SOSTDC1-producing follicular helper T cells promote regulatory follicular T cell differentiation , 2020, Science.

[21]  N. Bhowmick,et al.  The adaptor protein SHCA launches cancer invasion , 2020, The Journal of Biological Chemistry.

[22]  E. Nogales,et al.  Structural basis for dimerization quality control , 2020, Nature.

[23]  Jae-Bong Park,et al.  Regulation of RhoA GTPase and novel target proteins for ROCK , 2020, Small GTPases.

[24]  E. Gars,et al.  The life and death of the germinal center. , 2019, Annals of diagnostic pathology.

[25]  Í. Caruso,et al.  Grb2 dimer interacts with Coumarin through SH2 domains: A combined experimental and molecular modeling study , 2019, Heliyon.

[26]  J. Squire Special Issue: The Actin-Myosin Interaction in Muscle: Background and Overview , 2019, International journal of molecular sciences.

[27]  I. Lossos,et al.  Recent BCR stimulation induces a negative autoregulatory loop via FBXO10 mediated degradation of HGAL , 2019, Leukemia.

[28]  I. Lossos,et al.  Interplay between HGAL and Grb2 proteins regulates B-cell receptor signaling. , 2019, Blood advances.

[29]  C. Ottmann,et al.  Modulating protein-protein interaction networks in protein homeostasis. , 2019, Current opinion in chemical biology.

[30]  J. Cyster,et al.  B Cell Responses: Cell Interaction Dynamics and Decisions , 2019, Cell.

[31]  T. Sulea,et al.  The adaptor protein Ste50 directly modulates yeast MAPK signaling specificity through differential connections of its RA domain , 2019, Molecular biology of the cell.

[32]  M. Oda,et al.  Structural and functional properties of Grb2 SH2 dimer in CD28 binding , 2019, Biophysics and physicobiology.

[33]  Zhongyuan Wang,et al.  Chronic psychological stress impairs germinal center response by repressing miR-155 , 2019, Brain, Behavior, and Immunity.

[34]  Jae-Bong Park,et al.  Regulation of RhoA GTPase and various transcription factors in the RhoA pathway , 2018, Journal of cellular physiology.

[35]  David D. Thomas,et al.  Actin-Myosin Interaction: Structure, Function and Drug Discovery , 2018, International journal of molecular sciences.

[36]  S. Piccolo,et al.  YAP/TAZ upstream signals and downstream responses , 2018, Nature Cell Biology.

[37]  M. von Zastrow,et al.  Subcellular Organization of GPCR Signaling. , 2018, Trends in pharmacological sciences.

[38]  D. Dunson,et al.  Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma , 2017, Cell.

[39]  J. Cyster,et al.  Germinal centers: programmed for affinity maturation and antibody diversification. , 2017, Current opinion in immunology.

[40]  H. Urlaub,et al.  The Dok‐3/Grb2 adaptor module promotes inducible association of the lipid phosphatase SHIP with the BCR in a coreceptor‐independent manner , 2016, European journal of immunology.

[41]  A. Ridley,et al.  Regulating Rho GTPases and their regulators , 2016, Nature Reviews Molecular Cell Biology.

[42]  I. Lossos,et al.  GNA13 loss in germinal center B cells leads to impaired apoptosis and promotes lymphoma in vivo. , 2016, Blood.

[43]  Kenneth H. Roux,et al.  An improved smaller biotin ligase for BioID proximity labeling , 2016, Molecular biology of the cell.

[44]  K. Toellner,et al.  Regulation of germinal center B‐cell differentiation , 2016, Immunological reviews.

[45]  P. Mattila,et al.  Molecular Control of B Cell Activation and Immunological Synapse Formation , 2015, Traffic.

[46]  L. Staudt,et al.  A roadmap for discovery and translation in lymphoma. , 2015, Blood.

[47]  C. Hother,et al.  Differential Expression of miR-155 and miR-21 in Tumor and Stroma Cells in Diffuse Large B-Cell Lymphoma , 2015, Applied immunohistochemistry & molecular morphology : AIMM.

[48]  I. Lossos,et al.  HGAL localization to cell membrane regulates B-cell receptor signaling. , 2015, Blood.

[49]  Christopher M. Fife,et al.  Movers and shakers: cell cytoskeleton in cancer metastasis , 2014, British journal of pharmacology.

[50]  Y. Kwong,et al.  Methylation of miR-155-3p in mantle cell lymphoma and other non-Hodgkin's lymphomas , 2014, Oncotarget.

[51]  Adrien B. Larsen,et al.  Loss of signaling via Gα13 in germinal center B cell-derived lymphoma , 2014, Nature.

[52]  D. Voehringer,et al.  B‐cell‐intrinsic STAT6 signaling controls germinal center formation , 2014, European journal of immunology.

[53]  R. Tibshirani,et al.  LMO2 and BCL6 are associated with improved survival in primary central nervous system lymphoma , 2014, British journal of haematology.

[54]  N. Finley,et al.  Cardiac myosin binding protein-C: a structurally dynamic regulator of myocardial contractility , 2014, Pflügers Archiv - European Journal of Physiology.

[55]  Min Chen,et al.  Dynamic functions of RhoA in tumor cell migration and invasion , 2013, Small GTPases.

[56]  Ash A. Alizadeh,et al.  Germinal centre protein HGAL promotes lymphoid hyperplasia and amyloidosis via BCR-mediated Syk activation , 2012, Nature Communications.

[57]  C. Leslie,et al.  BCL6 positively regulates AID and germinal center gene expression via repression of miR-155 , 2012, The Journal of experimental medicine.

[58]  M. Mohammadi,et al.  Grb2, a Double-Edged Sword of Receptor Tyrosine Kinase Signaling , 2012, Science Signaling.

[59]  Michael D. Cahalan,et al.  A Decade of Imaging Cellular Motility and Interaction Dynamics in the Immune System , 2012, Science.

[60]  J. Cyster,et al.  S1PR2 links germinal center confinement and growth regulation , 2012, Immunological reviews.

[61]  B. Treanor B‐cell receptor: from resting state to activate , 2012, Immunology.

[62]  J. Cyster,et al.  Sphingosine-1-phosphate and lymphocyte egress from lymphoid organs. , 2012, Annual review of immunology.

[63]  Brian Burke,et al.  A promiscuous biotin ligase fusion protein identifies proximal and interacting proteins in mammalian cells , 2012, The Journal of cell biology.

[64]  I. Lossos,et al.  miR-155 regulates HGAL expression and increases lymphoma cell motility. , 2012, Blood.

[65]  J. Trewhella,et al.  The C0C1 fragment of human cardiac myosin binding protein C has common binding determinants for both actin and myosin. , 2011, Journal of molecular biology.

[66]  F. Lin,et al.  TRIP6: an adaptor protein that regulates cell motility, antiapoptotic signaling and transcriptional activity. , 2011, Cellular signalling.

[67]  I. Lossos,et al.  PRDM1/Blimp1 downregulates expression of germinal center genes LMO2 and HGAL , 2011, The FEBS journal.

[68]  H. Urlaub,et al.  B cell receptor-mediated antigen gathering requires ubiquitin ligase Cbl and adaptors Grb2 and Dok-3 to recruit dynein to the signaling microcluster. , 2011, Immunity.

[69]  Y. Zou,et al.  Growth-factor receptor-bound protein-2 (Grb2) signaling in B cells controls lymphoid follicle organization and germinal center reaction , 2011, Proceedings of the National Academy of Sciences.

[70]  I. Lossos BLIMP1 against lymphoma: The verdict is reached. , 2010, Cancer cell.

[71]  Govind Bhagat,et al.  BLIMP1 is a tumor suppressor gene frequently disrupted in activated B cell-like diffuse large B cell lymphoma. , 2010, Cancer cell.

[72]  J. Kutok,et al.  Constitutive canonical NF-κB activation cooperates with disruption of BLIMP1 in the pathogenesis of activated B cell-like diffuse large cell lymphoma. , 2010, Cancer cell.

[73]  Xiaoqing Lu,et al.  HGAL, a germinal center specific protein, decreases lymphoma cell motility by modulation of the RhoA signaling pathway. , 2010, Blood.

[74]  Michael Meyer-Hermann,et al.  Germinal Center Dynamics Revealed by Multiphoton Microscopy with a Photoactivatable Fluorescent Reporter , 2010, Cell.

[75]  D. Kono,et al.  Immune pathology associated with altered actin cytoskeleton regulation , 2010, Autoimmunity.

[76]  Jan Delabie,et al.  Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma , 2010, Nature.

[77]  Miguel Vicente-Manzanares,et al.  Non-muscle myosin II takes centre stage in cell adhesion and migration , 2009, Nature Reviews Molecular Cell Biology.

[78]  I. Lossos,et al.  Human germinal center-associated lymphoma protein expression is associated with improved failure-free survival in Brazilian patients with classical Hodgkin lymphoma , 2009, Leukemia & lymphoma.

[79]  Alan Hall,et al.  The cytoskeleton and cancer , 2009, Cancer and Metastasis Reviews.

[80]  I. Lossos,et al.  Expression of HGAL in primary cutaneous large B-cell lymphomas: evidence for germinal center derivation of primary cutaneous follicular lymphoma , 2008, Modern Pathology.

[81]  I. Lossos,et al.  Expression of the human germinal‐centre‐associated lymphoma protein in diffuse large B‐cell lymphomas in patients with rheumatoid arthritis , 2008, British journal of haematology.

[82]  I. Lossos,et al.  HGAL, a lymphoma prognostic biomarker, interacts with the cytoskeleton and mediates the effects of IL-6 on cell migration. , 2007, Blood.

[83]  David J J de Gorter,et al.  Lymphoma dissemination: the other face of lymphocyte homing. , 2007, Blood.

[84]  R. Adelstein,et al.  Loss of cell adhesion causes hydrocephalus in nonmuscle myosin II-B-ablated and mutated mice. , 2007, Molecular biology of the cell.

[85]  W. Chan,et al.  Studies of a germinal centre B‐cell expressed gene, GCET2, suggest its role as a membrane associated adapter protein , 2007, British journal of haematology.

[86]  N. Rajewsky,et al.  Regulation of the Germinal Center Response by MicroRNA-155 , 2007, Science.

[87]  Klaus Rajewsky,et al.  M17, a gene specific for germinal center (GC) B cells and a prognostic marker for GC B-cell lymphomas, is dispensable for the GC reaction in mice. , 2006, Blood.

[88]  J. Monroe ITAM-mediated tonic signalling through pre-BCR and BCR complexes , 2006, Nature Reviews Immunology.

[89]  Stefano Monti,et al.  Inactivation of the PRDM1/BLIMP1 gene in diffuse large B cell lymphoma , 2006, The Journal of experimental medicine.

[90]  L. Lanier,et al.  Role of ITAM‐containing adapter proteins and their receptors in the immune system and bone , 2005, Immunological reviews.

[91]  I. Lossos,et al.  Expression of the human germinal center-associated lymphoma (HGAL) protein identifies a subset of classic Hodgkin lymphoma of germinal center derivation and improved survival. , 2005, Blood.

[92]  Ralf Küppers,et al.  Mechanisms of B-cell lymphoma pathogenesis , 2005, Nature Reviews Cancer.

[93]  Yasodha Natkunam,et al.  Expression of the human germinal center-associated lymphoma (HGAL) protein, a new marker of germinal center B-cell derivation. , 2004, Blood.

[94]  K. Calame,et al.  B Lymphocyte-Induced Maturation Protein (Blimp)-1, IFN Regulatory Factor (IRF)-1, and IRF-2 Can Bind to the Same Regulatory Sites1 , 2004, The Journal of Immunology.

[95]  Kenneth M. Yamada,et al.  Defects in Cell Adhesion and the Visceral Endoderm following Ablation of Nonmuscle Myosin Heavy Chain II-A in Mice* , 2004, Journal of Biological Chemistry.

[96]  M. Reth,et al.  Perspectives on the nature of BCR-mediated survival signals. , 2004, Molecular cell.

[97]  L. Staudt,et al.  Two newly characterized germinal center B-cell-associated genes, GCET1 and GCET2, have differential expression in normal and neoplastic B cells. , 2003, The American journal of pathology.

[98]  Robert Tibshirani,et al.  HGAL is a novel interleukin-4-inducible gene that strongly predicts survival in diffuse large B-cell lymphoma. , 2003, Blood.

[99]  F. Sánchez‐Madrid,et al.  Regulation of microtubule‐organizing center orientation and actomyosin cytoskeleton rearrangement during immune interactions , 2002, Immunological reviews.

[100]  A. Tari,et al.  GRB2: a pivotal protein in signal transduction. , 2001, Seminars in oncology.

[101]  K. Tedford,et al.  Lsc is required for marginal zone B cells, regulation of lymphocyte motility and immune responses , 2001, Nature Immunology.

[102]  Shiaoching Gong,et al.  B Cell Development Is Arrested at the Immature B Cell Stage in Mice Carrying a Mutation in the Cytoplasmic Domain of Immunoglobulin β , 2001, The Journal of experimental medicine.

[103]  J. M. Bradshaw,et al.  Role of electrostatic interactions in SH2 domain recognition: salt-dependence of tyrosyl-phosphorylated peptide binding to the tandem SH2 domain of the Syk kinase and the single SH2 domain of the Src kinase. , 2000, Biochemistry.

[104]  Ash A. Alizadeh,et al.  Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling , 2000, Nature.

[105]  M. Kennedy,et al.  The rat brain postsynaptic density fraction contains a homolog of the drosophila discs-large tumor suppressor protein , 1992, Neuron.

[106]  Klaus Rajewsky,et al.  A B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin μ chain gene , 1991, Nature.

[107]  T. Matsuda,et al.  STAP-2 Adaptor Protein Regulates Multiple Steps of Immune and Inflammatory Responses. , 2021, Biological & pharmaceutical bulletin.

[108]  S. Watson,et al.  The N-terminal SH2 domain of Syk is required for (hem)ITAM, but not integrin, signaling in mouse platelets. , 2015, Blood.

[109]  L. Berthiaume,et al.  Post-translational myristoylation: Fat matters in cellular life and death. , 2011, Biochimie.

[110]  F. Bonilla,et al.  Adaptive immunity. , 2010, The Journal of allergy and clinical immunology.

[111]  D. Iber Formation of the B cell synapse: retention or recruitment? , 2004, Cellular and Molecular Life Sciences CMLS.

[112]  G. Cattoretti,et al.  Role of B-lymphocyte-induced maturation protein-1 in terminal differentiation of B cells and other cell lineages. , 1999, Cold Spring Harbor symposia on quantitative biology.