Signal
transduction
The N-terminal cytoplasmic region of LMP2A has
eight tyrosine residues,among them two with exact homology to the
Immunoglobulin Transactivation Motifs (ITAMs), that upon phosphorylation
bind the SH2 domains of the Syk tyrosine kinases and Y 112 motif that
binds the Src family kinase Lyn.
The LMP2A N-terminal region also has two conserved PPPPY motifs. We
have shown that the PPPPY motifs of LMP2A bind the WW domains of specific
E3 protein-ubiquitin ligases, including AIP4/Itch and KIAA0439, both
in vitro and in cultured B cells. In addition to a N-terminal C2 domain
and four WW domains, these proteins have a C-terminal Hect catalytic
domain implicated in the ubiquitination of target proteins. In cells
expressing LMP2A, AIP4/Itch induces ubiquitination of Lyn and Syk.
These results suggest that LMP2A serves as a molecular scaffold to
recruit both B cell tyrosine kinases and C2/WW/Hect domain E3 protein-ubiquitin
ligases, thereby promoting Lyn and Syk ubiquitination in a fashion
that may contribute to a block in B cell signaling. LMP2A may therefore
potentiate a normal mechanism in the regulation of B cell signaling
(Winberg et al., submitted; Matskova et al., submitted).
This work is done by G�sta Winberg, docent; Ludmilla Matskova; graduate
student; Ingemar Ernberg and FuChen, graduate student in close collaboration
with Tony Pawsons group in Toronto.