Tetraspanin CD37 directly mediates transduction of survival and apoptotic signals

Rosa Lapalombella; Yuh-Ying Yeh; Liwen Wang; Asha Ramanunni; Sarwish Rafiq; Shruti Jha; Justin Staubli; David M Lucas; Rajeswaran Mani; Sarah E M Herman; Amy J Johnson; Arletta Lozanski; Leslie Andritsos; Jeffrey Jones; Joseph M Flynn; Brian Lannutti; Peter Thompson; Paul Algate; Scott Stromatt; David Jarjoura; Xiaokui Mo; Dasheng Wang; Ching-Shih Chen; Gerard Lozanski; Nyla A Heerema; Susheela Tridandapani; Michael A Freitas; Natarajan Muthusamy; John C Byrd

doi:10.1016/j.ccr.2012.03.040

Tetraspanin CD37 directly mediates transduction of survival and apoptotic signals

Cancer Cell. 2012 May 15;21(5):694-708. doi: 10.1016/j.ccr.2012.03.040.

Authors

Rosa Lapalombella¹, Yuh-Ying Yeh¹, Liwen Wang², Asha Ramanunni¹, Sarwish Rafiq³, Shruti Jha¹, Justin Staubli³, David M Lucas⁴, Rajeswaran Mani⁵, Sarah E M Herman³, Amy J Johnson⁴, Arletta Lozanski¹, Leslie Andritsos¹, Jeffrey Jones¹, Joseph M Flynn¹, Brian Lannutti⁶, Peter Thompson⁷, Paul Algate⁸, Scott Stromatt⁸, David Jarjoura⁹, Xiaokui Mo⁹, Dasheng Wang¹⁰, Ching-Shih Chen⁴, Gerard Lozanski¹¹, Nyla A Heerema¹¹, Susheela Tridandapani¹², Michael A Freitas¹³, Natarajan Muthusamy¹⁴, John C Byrd¹⁵

Affiliations

¹ Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
² Department of Chemistry, The Ohio State University, Columbus, OH 43210, USA.
³ 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.
⁴ 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.
⁵ 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.
⁶ Gilead Pharmaceuticals Inc, Seattle, WA 98102, USA.
⁷ OrbiMed Advisors, LLC, New York, NY 10017, USA.
⁸ Emergent BioSolutions, Seattle, WA 98121-3460, USA.
⁹ Center for Biostatistics, The Ohio State University, Columbus, OH 43210, USA.
¹⁰ Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
¹¹ Department of Pathology, The Ohio State University, Columbus, OH 43210, USA.
¹² Division of Pulmonary Medicine, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
¹³ Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA.
¹⁴ 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: [email protected].
¹⁵ 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: [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Motifs
Amino Acid Sequence
Antigens, Neoplasm / chemistry
Antigens, Neoplasm / genetics
Antigens, Neoplasm / metabolism*
Apoptosis Regulatory Proteins / genetics
Apoptosis Regulatory Proteins / metabolism
Apoptosis* / drug effects
B-Lymphocytes / drug effects
B-Lymphocytes / metabolism*
B-Lymphocytes / pathology
Bcl-2-Like Protein 11
Cell Line, Tumor
Cell Survival
Chromatography, Liquid
Forkhead Box Protein O3
Forkhead Transcription Factors / metabolism
HEK293 Cells
Humans
Immunoglobulin G / pharmacology
Leukemia, Lymphocytic, Chronic, B-Cell / genetics
Leukemia, Lymphocytic, Chronic, B-Cell / metabolism*
Leukemia, Lymphocytic, Chronic, B-Cell / pathology
Membrane Microdomains / metabolism
Membrane Potential, Mitochondrial
Membrane Proteins / genetics
Membrane Proteins / metabolism
Molecular Sequence Data
Nanotechnology
Phosphatidylinositol 3-Kinase / metabolism
Phosphorylation
Protein Transport
Proteomics / methods
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism
RNA Interference
Recombinant Fusion Proteins / pharmacology
Signal Transduction* / drug effects
Tandem Mass Spectrometry
Tetraspanins / chemistry
Tetraspanins / genetics
Tetraspanins / metabolism*
Time Factors
Transfection
Tyrosine

Substances

Antigens, Neoplasm
Apoptosis Regulatory Proteins
BCL2L11 protein, human
Bcl-2-Like Protein 11
CD37 protein, human
FOXO3 protein, human
Forkhead Box Protein O3
Forkhead Transcription Factors
Immunoglobulin G
Membrane Proteins
Proto-Oncogene Proteins
Recombinant Fusion Proteins
TRU 016
Tetraspanins
Tyrosine
Phosphatidylinositol 3-Kinase

Abstract

Publication types

MeSH terms

Substances

Grants and funding