SYK is upstream of phosphoinositide 3-kinase in B cell receptor signaling

被引:154
作者
Beitz, LO
Fruman, DA
Kurosaki, T
Cantley, LC
Scharenberg, AM [1 ]
机构
[1] Harvard Univ, Sch Med, Lab Allergy & Immunol, Boston, MA 02215 USA
[2] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Signal Transduct, Boston, MA 02215 USA
[3] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02215 USA
[4] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02215 USA
[5] Kansai Med Univ, Dept Mol Genet, Moriguchi, Osaka 570, Japan
关键词
D O I
10.1074/jbc.274.46.32662
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
We have recently demonstrated that the D3-phosphoinositide phosphatidylinositol 3,4,5-trisphosphate (PtdIns-3,4,5-P-3) is critical for producing sustained calcium signals through its role in promoting the function of TEC family tyrosine kinases such as Bruton's tyrosine kinase. Although PtdIns-3,4,5-P-3 can potentially be synthesized by any of several types of phosphoinositide 3-kinases (PI3Ks), B cell receptor (BCR)-induced PtdIns-3,4,5-P-3 production is thought to occur primarily through the activation of the class Ia (p85/p110) PI3Ks. This process has been proposed to be mediated by an interaction between the Src family kinase LYN and the p85 subunit of FISH and/or through p85 membrane recruitment mediated by CBL and/or CD19. However, calcium signaling and other PI3K-dependent signals are relatively preserved in a LYN kinase-deficient B lymphocyte cell line, suggesting that an alternative pathway for PI3K, activation exists. As SYK/ZAP70 kinases are upstream from many BCR-initiated signaling events, we directly analyzed SYM-dependent accumulation of both PtdIns-3,4,5-P-3 and PtdIns-3,4-P-2 in B cell receptor signaling using both dominant negative and genetic knockout approaches. Both methods indicate that SYK is upstream of, and necessary for, a significant portion of BCR-induced PtdIns-3,4,5-P-3 production. Whereas CD19 does not appear 60 be involved in this SYM-dependent pathway, the SYK substrate CEL is likely involved as the dominant negative SYK markedly attenuates CBL tyrosine phosphorylation and completely blocks the BCR-dependent association of CBL with p85 PI3K.
引用
收藏
页码:32662 / 32666
页数:5
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