A conditional form of Bruton's tyrosine kinase is sufficient to activate multiple downstream signaling pathways via PLC Gamma 2 in B cells

BMC Immunology - 2001
Michael G Tomlinson1,2, Douglas B Woods2,3, Martin McMahon4,2, Matthew I Wahl5, Owen N Witte5, Tomohiro Kurosaki6, Joseph B Bolen2,4, James A Johnston2,7
1Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, USA
2DNAX Research Institute of Molecular and Cellular Biology, Palo Alto, USA
3National Cancer Institute-FCRDC, Frederick, USA
4Cancer Research Institute, UCSF/Mt. Zion Cancer Center, San Francisco, USA
5Howard Hughes Medical Institute, and the Department of Microbiology, Immunology, and Molecular Genetics, University of California at Los Angeles, Los Angeles, USA
6Department of Molecular Genetics, Kansai Medical University, Moriguchi 570, Japan
7Department of Immunology, Whitla Building, Queen's University Belfast, Belfast BT9 7BL, Northern Ireland

Tóm tắt

Bruton's tyrosine kinase (Btk) is essential for B cell development and function. Mutations of Btk elicit X-linked agammaglobulinemia in humans and X-linked immunodeficiency in the mouse. Btk has been proposed to participate in B cell antigen receptor-induced signaling events leading to activation of phospholipase C-γ2 (PLCγ2) and calcium mobilization. However it is unclear whether Btk activation is alone sufficient for these signaling events, and whether Btk can activate additional pathways that do not involve PLCγ2. To address such issues we have generated Btk:ER, a conditionally active form of the kinase, and expressed it in the PLCγ2-deficient DT40 B cell line. Activation of Btk:ER was sufficient to induce multiple B cell signaling pathways in PLCγ2-sufficient DT40 cells. These included tyrosine phosphorylation of PLCγ2, mobilization of intracellular calcium, activation of extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathways, and apoptosis. In DT40 B cells deficient for PLCγ2, Btk:ER activation failed to induce the signaling events described above with the consequence that the cells failed to undergo apoptosis. These data suggest that Btk:ER regulates downstream signaling pathways primarily via PLCγ2 in B cells. While it is not known whether activated Btk:ER precisely mimics activated Btk, this conditional system will likely facilitate the dissection of the role of Btk and its family members in a variety of biological processes in many different cell types.

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