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,
Departments of
*
Medicine and
Microbiology, University of Alabama, Birmingham, AL 35294; and
Birmingham Veterans Affairs Medical Center, Birmingham, AL 35233
CD19 is a coreceptor on B cells that enhances the increase in
cytoplasmic calcium and ERK2 activation when coligated with the B cell
Ag receptor. Constructs containing point mutations and truncations were
expressed in Daudi human B lymphoblastoid cells to systematically
determine the requirement for individual CD19 cytoplasmic tyrosines in
these responses. Evidence for activity was found for Y330, Y360, and
Y421 as well as that previously published for Y391. Precipitates formed
with phosphopeptides consisting of CD19 sequences flanking these
residues were used to screen for cytoplasmic proteins that mediate
signaling. Phosphopeptide Y330 precipitated Grb2 and Sos, whereas
phosphopeptides Y391 and Y421 both precipitated Vav and phospholipase
C-
2. These molecules also were found associated with native CD19. In
mapping studies with altered constructs, CD19 Y330 and/or Y360 were
necessary for binding Grb2 and Sos. Vav associated with CD19
constitutively in unstimulated cells by a tyrosine-independent
mechanism requiring the portion of CD19 encoded by exons 9–12. After B
cell Ag receptor stimulation, Vav association was tyrosine-dependent,
but binding was influenced by multiple residues. However, when
maximally phosphorylated by pervanadate, Y391 and, to a lesser extent,
Y421 were sufficient. CD19 Y391 was also both necessary and sufficient
for binding phospholipase C-2. Thus, different tyrosines along the
CD19 cytoplasmic domain provide scaffolding for the formation of
complexes of different signaling molecules.
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