BLNK binds active H-Ras to promote B cell receptor-mediated capping and ERK activation.
Cross-linked B cell receptor (BCR) aggregates on the cell surface, then assembles into the "cap" where Ras is co-localized, and transduces various intracellular signals including Ras-ERK activation. BCR signals induce proliferation, differentiation, or apoptosis of B cells depending on their maturational stage. The adaptor protein BLNK binds various signaling proteins and Igalpha, a signaling subunit of the BCR complex, and plays an important role in the BCR signal transduction. BLNK was shown to be required for activation of ERK, but not of Ras, after BCR cross-linking, raising a question how BLNK facilitates ERK activation. Here we demonstrate that BLNK binds the active form of H-Ras, and their binding is facilitated by BCR cross-linking. We have identified a 10-amino acid Ras-binding domain within BLNK that is necessary for restoration of BCR-mediated ERK activation in BLNK-deficient B cells and for anti-apoptotic signaling. The Ras-binding domain fused with a CD8alpha-Igalpha chimeric receptor could induce prolonged ERK phosphorylation, transcriptional activation of Elk1, as well as the capping of the receptor in BLNK-deficient B cells. These results indicate that BLNK recruits active H-Ras to the BCR complex, which is essential for sustained surface expression of BCR in the form of the cap and for the signal leading to functional ERK activation.
Imamura
Yasuhiro
Y
Division of Molecular Biology, Research Institute for Biological Sciences, Tokyo University of Science, 2669 Yamazaki, Noda, Chiba 278-0022, Japan.
Oda
Akihisa
A
Katahira
Takashi
T
Bundo
Kenji
K
Pike
Kelly A
KA
Ratcliffe
Michael J H
MJ
Kitamura
Daisuke
D
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D016827:CD8 Antigens / Q000096:biosynthesis; D019556:COS Cells; D002454:Cell Differentiation; D049109:Cell Proliferation; D002645:Chickens; D002522:Chlorocebus aethiops; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C113939:B cell linker protein; D016827:CD8 Antigens; D011947:Receptors, Antigen, B-Cell; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins