title: Amplification of B cell receptor-Erk signaling by Rasgrf-1 overexpression in chronic lymphocytic leukemia.
abstract: Rasgrf-1 is a guanine exchange factor (GEF) that catalyzes the exchange of GDP for GTP. In a RNA microarray analysis of chronic lymphocytic leukemia (CLL) specimens (n = 5), this gene was found to be overexpressed in CLL as compared to normal peripheral blood mononuclear cell (PBMC) CD19 + B cells (n = 3). CLL specimens (n = 29) expressed Rasgrf-1 RNA at levels 5-300-fold higher as compared to normal B cells. CLL specimens expressed a 75 kDa isoform that was smaller than the expected full-length protein (140 kDa) and the truncated variant had higher GEF activity. Knockdown of Rasgrf-1 in CLL specimens inhibited active GTP-bound Ras and the Ras/Erk/mitogen-activated protein kinase (MAPK) pathway. Rasgrf-1 was phosphorylated and activated by B cell receptor (BCR) signaling that increased its GEF function, and this phosphorylation was blocked by Src and Bruton's tyrosine kinase (BTK) inhibitors. Rasgrf-1 is a novel GEF protein that has a role in BCR signaling and its overexpression further activates the Ras/Erk/MAPK pathway in CLL specimens.
authors.affiliation: Division of Hematology-Oncology, Greater Los Angeles VA Healthcare Center, UCLA School of Medicine , Los Angeles, CA , USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Liao
authors.forename: Gwen
authors.initials: G
authors.lastname: Jordaan
authors.forename: Natalie
authors.initials: N
authors.lastname: Coriaty
authors.forename: Sanjai
authors.initials: S
authors.lastname: Sharma
mesh_terms: D015870:Gene Expression; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D009367:Neoplasm Staging; D010766:Phosphorylation; D012333:RNA, Messenger; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism; D020666:ras-GRF1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D011947:Receptors, Antigen, B-Cell; D020666:ras-GRF1; D018631:ras Proteins
keywords: B cell receptor; CLL; Erk pathway; Rasgrf-1; guanine exchange factor