title: Tetraspanin CD37 directly mediates transduction of survival and apoptotic signals.
abstract: Tetraspanins are commonly believed to act only as "molecular facilitators," with no direct role in signal transduction. We herein demonstrate that upon ligation, CD37, a tetraspanin molecule expressed on mature normal and transformed B cells, becomes tyrosine phosphorylated, associates with proximal signaling molecules, and initiates a cascade of events leading to apoptosis. Moreover, we have identified two tyrosine residues with opposing regulatory functions: one lies in the N-terminal domain of CD37 in a predicted "ITIM-like" motif and mediates SHP1-dependent death, whereas the second lies in a predicted "ITAM motif" in the C-terminal domain of CD37 and counteracts death signals by mediating phosphatidylinositol 3-kinase-dependent survival.
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Rosa
authors.initials: R
authors.lastname: Lapalombella
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Yuh-Ying
authors.initials: YY
authors.lastname: Yeh
authors.affiliation: Department of Chemistry, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Liwen
authors.initials: L
authors.lastname: Wang
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Asha
authors.initials: A
authors.lastname: Ramanunni
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA; The Integrated Biomedical Research Graduate Program, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Sarwish
authors.initials: S
authors.lastname: Rafiq
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Shruti
authors.initials: S
authors.lastname: Jha
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA; The Integrated Biomedical Research Graduate Program, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Staubli
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA; Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Lucas
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA; Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Rajeswaran
authors.initials: R
authors.lastname: Mani
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA; The Integrated Biomedical Research Graduate Program, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Sarah E M
authors.initials: SEM
authors.lastname: Herman
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA; Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Johnson
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Arletta
authors.initials: A
authors.lastname: Lozanski
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Leslie
authors.initials: L
authors.lastname: Andritsos
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Jones
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Flynn
authors.affiliation: Gilead Pharmaceuticals Inc, Seattle, WA 98102, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Lannutti
authors.affiliation: OrbiMed Advisors, LLC, New York, NY 10017, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Thompson
authors.affiliation: Emergent BioSolutions, Seattle, WA 98121-3460, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Algate
authors.affiliation: Emergent BioSolutions, Seattle, WA 98121-3460, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Stromatt
authors.affiliation: Center for Biostatistics, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: David
authors.initials: D
authors.lastname: Jarjoura
authors.affiliation: Center for Biostatistics, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Mo
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Dasheng
authors.initials: D
authors.lastname: Wang
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA; Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Gerard
authors.initials: G
authors.lastname: Lozanski
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Nyla A
authors.initials: NA
authors.lastname: Heerema
authors.affiliation: Division of Pulmonary Medicine, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Susheela
authors.initials: S
authors.lastname: Tridandapani
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Freitas
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA; Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210, USA; Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA. Electronic address: raj.muthusamy@osumc.edu.
authors.forename: Natarajan
authors.initials: N
authors.lastname: Muthusamy
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA; Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210, USA; Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA. Electronic address: john.byrd@osumc.edu.
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000072224:Bcl-2-Like Protein 11; D045744:Cell Line, Tumor; D002470:Cell Survival; D002853:Chromatography, Liquid; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D021962:Membrane Microdomains / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D036103:Nanotechnology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010766:Phosphorylation; D021381:Protein Transport; D040901:Proteomics / Q000379:methods; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D053719:Tandem Mass Spectrometry; D059470:Tetraspanins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D014443:Tyrosine
chemical_list: D000951:Antigens, Neoplasm; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C059071:CD37 protein, human; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D007074:Immunoglobulin G; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; C547387:TRU 016; D059470:Tetraspanins; D014443:Tyrosine; D058539:Phosphatidylinositol 3-Kinase