Amplification of B cell receptor-Erk signaling by Rasgrf-1 overexpression in chronic lymphocytic leukemia

Leuk Lymphoma. 2014 Dec;55(12):2907-16. doi: 10.3109/10428194.2014.898759. Epub 2014 Apr 2.

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.

Keywords: B cell receptor; CLL; Erk pathway; Rasgrf-1; guanine exchange factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Gene Expression Profiling
  • Gene Expression*
  • Gene Knockdown Techniques
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
  • Leukemia, Lymphocytic, Chronic, B-Cell / metabolism*
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology
  • MAP Kinase Signaling System*
  • Models, Biological
  • Neoplasm Staging
  • Phosphorylation
  • RNA, Messenger
  • Receptors, Antigen, B-Cell / metabolism*
  • ras Proteins / genetics
  • ras Proteins / metabolism
  • ras-GRF1 / genetics*
  • ras-GRF1 / metabolism

Substances

  • RNA, Messenger
  • Receptors, Antigen, B-Cell
  • ras-GRF1
  • ras Proteins