SYK is upstream of phosphoinositide 3-kinase in B cell receptor signaling.
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 PI3K 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 SYK-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 to be involved in this SYK-dependent pathway, the SYK substrate CBL 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.
Beitz
L O
LO
Laboratory of Allergy, Beth Israel Deaconness Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Fruman
D A
DA
Kurosaki
T
T
Cantley
L C
LC
Scharenberg
A M
AM
D000818:Animals; D018941:Antigens, CD19 / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins; D008214:Lymphocytes; D051379:Mice; D050722:Oncogene Protein v-cbl; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D015682:Retroviridae Proteins, Oncogenic / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D000072377:Syk Kinase
D018941:Antigens, CD19; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D050722:Oncogene Protein v-cbl; D018129:Phosphatidylinositol Phosphates; D015682:Retroviridae Proteins, Oncogenic; C060974:phosphatidylinositol 3,4,5-triphosphate; C060980:phosphatidylinositol 3,4-diphosphate; D019000:Phosphotyrosine; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D002118:Calcium