title: The tetraspanin CD37 orchestrates the α(4)β(1) integrin-Akt signaling axis and supports long-lived plasma cell survival.
abstract: Signaling by the serine and threonine kinase Akt (also known as protein kinase B), a pathway that is common to all eukaryotic cells, is central to cell survival, proliferation, and gene induction. We sought to elucidate the mechanisms underlying regulation of the kinase activity of Akt in the immune system. We found that the four-transmembrane protein CD37 was essential for B cell survival and long-lived protective immunity. CD37-deficient (Cd37(-/-)) mice had reduced numbers of immunoglobulin G (IgG)-secreting plasma cells in lymphoid organs compared to those in wild-type mice, which we attributed to increased apoptosis of plasma cells in the germinal centers of the spleen, areas in which B cells proliferate and are selected. CD37 was required for the survival of IgG-secreting plasma cells in response to binding of vascular cell adhesion molecule 1 to the α(4)β(1) integrin. Impaired α(4)β(1) integrin-dependent Akt signaling in Cd37(-/-) IgG-secreting plasma cells was the underlying cause responsible for impaired cell survival. CD37 was required for the mobility and clustering of α(4)β(1) integrins in the plasma membrane, thus regulating the membrane distribution of α(4)β(1) integrin necessary for activation of the Akt survival pathway in the immune system.
authors.affiliation: Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen 6525 GA, The Netherlands.
authors.forename: Annemiek B
authors.initials: AB
authors.lastname: van Spriel
authors.forename: Sandra
authors.initials: S
authors.lastname: de Keijzer
authors.forename: Alie
authors.initials: A
authors.lastname: van der Schaaf
authors.forename: Kate H
authors.initials: KH
authors.lastname: Gartlan
authors.forename: Mariam
authors.initials: M
authors.lastname: Sofi
authors.forename: Amanda
authors.initials: A
authors.lastname: Light
authors.forename: Peter C
authors.initials: PC
authors.lastname: Linssen
authors.forename: Jan B
authors.initials: JB
authors.lastname: Boezeman
authors.forename: Malou
authors.initials: M
authors.lastname: Zuidscherwoude
authors.forename: Inge
authors.initials: I
authors.lastname: Reinieren-Beeren
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cambi
authors.forename: Fabienne
authors.initials: F
authors.lastname: Mackay
authors.forename: David M
authors.initials: DM
authors.lastname: Tarlinton
authors.forename: Carl G
authors.initials: CG
authors.lastname: Figdor
authors.forename: Mark D
authors.initials: MD
authors.lastname: Wright
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D018858:Germinal Center / Q000276:immunology / Q000378:metabolism; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D039041:Integrin alpha4beta1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010950:Plasma Cells / Q000276:immunology* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D059470:Tetraspanins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D000951:Antigens, Neoplasm; C504565:Cd37 protein, mouse; D007074:Immunoglobulin G; D039041:Integrin alpha4beta1; D059470:Tetraspanins; D051057:Proto-Oncogene Proteins c-akt