title: Global phosphoproteomic profiling reveals distinct signatures in B-cell non-Hodgkin lymphomas.
abstract: Deregulation of signaling pathways controlled by protein phosphorylation underlies the pathogenesis of hematological malignancies; however, the extent to which deregulated phosphorylation may be involved in B-cell non-Hodgkin lymphoma (B-NHL) pathogenesis is largely unknown. To identify phosphorylation events important in B-NHLs, we performed mass spectrometry-based, label-free, semiquantitative phosphoproteomic profiling of 11 cell lines derived from three B-NHL categories: Burkitt lymphoma, follicular lymphoma, and mantle-cell lymphoma. In all, 6579 unique phosphopeptides, corresponding to 1701 unique phosphorylated proteins, were identified and quantified. The data are available via ProteomeXchange with identifier PXD000658. Hierarchical clustering highlighted distinct phosphoproteomic signatures associated with each lymphoma subtype. Interestingly, germinal center-derived B-NHL cell lines were characterized by phosphorylation of proteins involved in the B-cell receptor signaling. Of these proteins, phosphoprotein associated with glycosphingolipid-enriched microdomains 1 (PAG1) was identified with the most phosphorylated tyrosine peptides in Burkitt lymphoma and follicular lymphoma. PAG1 knockdown resulted in perturbation of the tyrosine phosphosignature of B-cell receptor signaling components. Significantly, PAG1 knockdown increased cell proliferation and response to antigen stimulation of these germinal center-derived B-NHLs. These data provide a detailed annotation of phosphorylated proteins in human lymphoid cancer. Overall, our study revealed the utility of unbiased phosphoproteome interrogation in characterizing signaling networks that may provide insights into pathogenesis mechanisms in B-cell lymphomas.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Delphine
authors.initials: D
authors.lastname: Rolland
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Venkatesha
authors.initials: V
authors.lastname: Basrur
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Kevin
authors.initials: K
authors.lastname: Conlon
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan; Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wolfe
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Damian
authors.initials: D
authors.lastname: Fermin
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan; Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Alexey I
authors.initials: AI
authors.lastname: Nesvizhskii
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan; Center for Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Megan S
authors.initials: MS
authors.lastname: Lim
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan; Center for Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan; Center for Protein Folding Disease, University of Michigan Medical School, Ann Arbor, Michigan. Electronic address: kojoelen@umich.edu.
authors.forename: Kojo S J
authors.initials: KS
authors.lastname: Elenitoba-Johnson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016000:Cluster Analysis; D055785:Gene Knockdown Techniques; D018858:Germinal Center / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016393:Lymphoma, B-Cell / Q000175:diagnosis / Q000378:metabolism*; D008228:Lymphoma, Non-Hodgkin / Q000175:diagnosis / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D008954:Models, Biological; D010748:Phosphopeptides / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D040901:Proteomics / Q000379:methods*; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000951:Antigens, Neoplasm; D008565:Membrane Proteins; C498710:PAG1 protein, human; D010748:Phosphopeptides; D010750:Phosphoproteins; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases