The SRC family kinase LYN redirects B cell receptor signaling in human SLP65-deficient B cell lymphoma cells.
SLP65 represents a critical component in (pre-) B cell receptor signal transduction but is compromised in a subset of pre-B cell-derived acute lymphoblastic leukemia. Based on these findings, we investigated (i.) whether SLP65-deficiency also occurs in mature B cell-derived lymphoma and (ii.) whether SLP65-deficient B cell lymphoma cells use an alternative B cell receptor signaling pathway in the absence of SLP65. Indeed, expression of SLP65 protein was also missing in a fraction of B cell lymphoma cases. While SLP65 is essential for B cell receptor-induced Ca2+ mobilization in normal B cells, B cell receptor engagement in SLP65-deficient as compared to SLP65-reconstituted B cell lymphoma cells resulted in an accelerated yet shortlived Ca2+-signal. B cell receptor engagement of SLP65-deficient lymphoma cells involves SRC kinase activation, which is critical for B cell receptor-dependent Ca2+-mobilisation in the absence but not in the presence of SLP65. As shown by RNA interference, the SRC kinase LYN is required for B cell receptor-induced Ca2+ release in SLP65-deficient B cell lymphoma cells but dispensable after SLP65-reconstitution. B cell receptor engagement in SLP65-deficient B cell lymphoma cells also resulted in tyrosine-phosphorylation of the proliferation- and survival-related MAPK1 and STAT5 molecules, which was sensitive to silencing of the SRC kinase LYN. Inhibition of SRC kinase activity resulted in growth arrest and cell death specifically in SLP65-deficient lymphoma cells. These findings indicate that LYN can short-circuit conventional B cell receptor signaling in SLP65-deficient B cell lymphoma cells and thereby promote activation of survival and proliferation-related molecules.
Laboratory for Molecular Stem Cell Biology, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, and Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel, Germany.
M
M
Sprangers
N
N
Feldhahn
S
S
Herzog
M-L
ML
Hansmann
M
M
Reppel
J
J
Hescheler
H
H
Jumaa
R
R
Siebert
M
M
Müschen
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D006801:Humans; D016393:Lymphoma, B-Cell / Q000201:enzymology* / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C113939:B cell linker protein; D050799:STAT5 Transcription Factor; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D020928:Mitogen-Activated Protein Kinases