The tyrosine kinases Syk and Lyn exert opposing effects on the activation of protein kinase Akt/PKB in B lymphocytes.
The protein kinase Akt/PKB is a crucial regulator of cell survival in response to mitogenic signals. The increased kinase activity of v-akt, an oncogenic form of Akt/PKB, causes mouse T cell lymphoma, and overexpression of Akt/PKB is associated with progression of several tumor types in human. In this study, we demonstrate that ligation of B cell antigen receptor (BCR) leads to activation of Akt/PKB in B lymphocytes. BCR-induced activation of Akt/PKB required the tyrosine kinase Syk, which was not previously known to regulate Akt/PKB. In contrast, BCR crosslinking of Lyn-deficient B cells resulted in markedly enhanced hyperphosphorylation and activation of Akt/PKB compared with wild-type B cells, indicating that this Src-family kinase acts as an endogenous antagonist of BCR-induced Akt/PKB activation. Lyn inhibited Akt/PKB additively with an okadaic acid-sensitive endogenous phosphatase(s). Expression of exogenous Lyn in mutant cells restored normal BCR-induced phosphorylation of Akt/PKB. Negative regulation of Akt/PKB by Lyn was not dependent on the protein phosphatases SHP-1, SHP-2, or SHIP. Our results show that Lyn provides a mechanism for negative regulation and opposes the effect of Syk on BCR-mediated activation of Akt/PKB. Deregulation of Akt/PKB correlates with the hyperresponsiveness of B cells from Lyn-deficient mice stimulated by BCR crosslinking and may contribute to the autoimmune syndrome that develops in Lyn-deficient animals.
Li
H L
HL
Wistar Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
Davis
W W
WW
Whiteman
E L
EL
Birnbaum
M J
MJ
Puré
E
E
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D001402:B-Lymphocytes / Q000201:enzymology* / Q000276:immunology; D002460:Cell Line; D002645:Chickens; D004789:Enzyme Activation / Q000276:immunology; D004792:Enzyme Precursors / Q000276:immunology / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D000072377:Syk Kinase; D019061:src-Family Kinases / Q000276:immunology / Q000378:metabolism*
D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D019061:src-Family Kinases; D064413:3-Phosphoinositide-Dependent Protein Kinases; D017346:Protein Serine-Threonine Kinases