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ZAP-70 Enhances CD79b Phosphorylation

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[2799] Expression of ZAP-70 in Chronic Lymphocytic Leukemia Cells

Enhances CD79b Phosphorylation Following Surface IgM Ligation.

Session Type: Poster Session, Board #28-III

Liguang Chen, Apgar, Li Tang, J. Kipps s UCSD Cancer

Center, University of California, San Diego, La Jolla, CA, USA; Cell

Signaling Research, BD Pharmingen, San Diego, CA, USA

CD79b is B-cell surface molecule that non-covalently associates with

CD79a and surface immunoglobulin (sIg), which together serve as the B-

cell receptor complex (BCR).

Both CD79a and CD79b have cytosolic

immunoreceptor tyrosine-based activation motifs (ITAMs) that can

become phosphorylated following sIg ligation, thereby allowing for

recruitment to the BCR complex of cytosolic kinases, such as p72Syk ,

which then can initiate downstream intracellular signaling events.

Compared to normal B cells, chronic lymphocytic leukemia (CLL) B

cells typically expresses low levels of CD79b, which is speculated to

contribute to the relatively poor capacity of CLL cells to initiate

intracellular signaling following BCR ligation despite having

apparently adequate levels of p72Syk.

BCR signaling in CLL cells can

be enhanced by expression of the zeta-associated protein of 70 kD

(ZAP-70), a tyrosine kinase that initially was identified in T cells,

where it plays a critical role in the phosphorylation of ITAMs of the

accessory molecules of the T-cell receptor (TCR) complex for antigen

following TCR ligation.

We investigated for phosphorylation of CD79b

following BCR ligation with F(ab)2 anti-mu antibody in CLL cell

samples that did or did not express ZAP-70. All CLL cell samples

expressed similar amounts of surface IgM and p72Syk, as assessed via

flow cytometry and immunoblot analysis. Within 10 minutes after

treatment with anti-mu the CLL cell samples that expressed ZAP-70 (n

=

28) experienced a mean increase in phosphorylation of CD79b of 21.5%

( 14.0% S.D.), which was significantly greater than the 7.5% increase

( 7.9% S.D.) experienced by similarly treated CLL cell samples that

did not express ZAP-70 (n = 19) (P< 0.01). Immune precipitation

studies demonstrated association of CD79b with p72Syk in CLL B cells.

CLL cell samples (n = 5) lacking expression of ZAP-70 were

transfected with a control vector or an expression vector encoding

ZAP-70, allowing us to examine the effect that engineered-expression

of ZAP-70 has on CD79 phosphorylation following treatment with anti-

mu.

Anti-mu treatment induced significantly higher mean levels of CD79b

phosphorylation in CLL samples made to express ZAP-70 (33% 16%) than

in control mock-transfected CLL cells (4% 2%). This also was

associated with enhanced anti- induced phosphorylation of p72Syk.

We

conclude that expression of ZAP-70 in CLL B cells enhances

phosphorylation of the accessory molecules in the BCR complex

following sIg ligation, potentially allowing for improved recruitment

of cytosolic kinases and adapter proteins to these accessory

molecules for enhanced BCR signaling.

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