title: Sprouty 2: a novel attenuator of B-cell receptor and MAPK-Erk signaling in CLL.
abstract: Clinical heterogeneity is a major barrier to effective treatment of chronic lymphocytic leukemia (CLL). Emerging evidence suggests that constitutive activation of various signaling pathways like mitogen-activated protein kinase-extracellular signal-regulated kinase (MAPK-Erk) signaling plays a role in the heterogeneous clinical outcome of CLL patients. In this study, we have investigated the role of Sprouty (SPRY)2 as a negative regulator of receptor and nonreceptor tyrosine kinase signaling in the pathogenesis of CLL. We show that SPRY2 expression is significantly decreased in CLL cells, particularly from poor-prognosis patients compared with those from good-prognosis patients. Overexpression of SPRY2 in CLL cells from poor-prognosis patients increased their apoptosis. Conversely, downregulation of SPRY2 in CLL cells from good-prognosis patients resulted in increased proliferation. Furthermore, CLL cells with low SPRY2 expression grew more rapidly in a xenograft model of CLL. Strikingly, B-cell-specific transgenic overexpression of spry2 in mice led to a decrease in the frequency of B1 cells, the precursors of CLL cells in rodents. Mechanistically, we show that SPRY2 attenuates the B-cell receptor (BCR) and MAPK-Erk signaling by binding to and antagonizing the activities of RAF1, BRAF, and spleen tyrosine kinase (SYK) in normal B cells and CLL cells. We also show that SPRY2 is targeted by microRNA-21, which in turn leads to increased activity of Syk and Erk in CLL cells. Taken together, these results establish SPRY2 as a critical negative regulator of BCR-mediated MAPK-Erk signaling in CLL, thereby providing one of the molecular mechanisms to explain the clinical heterogeneity of CLL.
authors.affiliation: Department of Genetics, Cell Biology and Anatomy.
authors.forename: Ashima
authors.initials: A
authors.lastname: Shukla
authors.affiliation: Department of Genetics, Cell Biology and Anatomy.
authors.forename: Karan
authors.initials: K
authors.lastname: Rai
authors.affiliation: Department of Genetics, Cell Biology and Anatomy.
authors.forename: Vipul
authors.initials: V
authors.lastname: Shukla
authors.affiliation: Department of Genetics, Cell Biology and Anatomy.
authors.forename: Nagendra K
authors.initials: NK
authors.lastname: Chaturvedi
authors.affiliation: Department of Internal Medicine, Section of Oncology and Hematology.
authors.forename: R Gregory
authors.initials: RG
authors.lastname: Bociek
authors.affiliation: Department of Pathology and Microbiology, College of Medicine, and.
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Pirruccello
authors.affiliation: Department of Genetics, Cell Biology and Anatomy, Department of Pathology and Microbiology, College of Medicine, and Eppley Institute for Research in Cancer and Allied Disease, University of Nebraska Medical Center, Omaha, NE.
authors.forename: Hamid
authors.initials: H
authors.lastname: Band
authors.affiliation: Department of Genetics, Cell Biology and Anatomy.
authors.forename: Runqing
authors.initials: R
authors.lastname: Lu
authors.affiliation: Department of Genetics, Cell Biology and Anatomy.
authors.forename: Shantaram S
authors.initials: SS
authors.lastname: Joshi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D017346:Protein Serine-Threonine Kinases; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000378:metabolism*; D000072377:Syk Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011947:Receptors, Antigen, B-Cell; C485561:SPRY2 protein, human; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C482119:BRAF protein, human; C482120:Braf protein, mouse; D017346:Protein Serine-Threonine Kinases; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; C118389:Spry2 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases
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