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Receptor-Mediated Phagocytosis by Transforming Mutants of Cbl1
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
Phagocytosis mediated by Fc
R plays an important role in
host defense. The molecular events involved in this process have not
been completely defined. The adapter protein Cbl has been implicated in
FcR signaling, but the function of Cbl in phagocytosis is unknown.
Here we show that overexpression of the transforming mutants of Cbl,
Cbl-70Z, and v-Cbl, but not wild-type (wt) Cbl, enhance phagocytosis
mediated by FcR in COS cells. Cbl-70Z, but not Cbl-wt, also enhanced
FcR-mediated phagocytosis in P388D1 murine macrophage cells. Cbl-70Z
did not affect tyrosine phosphorylation or in vitro kinase activity of
Syk, indicating that Syk may not be the direct target of Cbl-70Z in the
enhancement of phagocytosis. A point mutation (G306E) in the
phosphotyrosine domain of Cbl-70Z, as well as a C-terminal 67-aa
deletion, partially abolished the enhancing effect on FcR-mediated
phagocytosis. A double mutant of Cbl-70Z containing both the G306E
mutation and the C-terminal deletion completely lacked the ability to
enhance phagocytosis. Thus, both the phosphotyrosine binding domain and
the carboxyl-terminal tail were required for optimal enhancement of
phagocytosis by Cbl-70Z. Functional phosphatidylinositol 3-kinase was
required for Cbl-70Z to enhance phagocytosis, since wortmannin, a
phosphatidylinositol 3-kinase inhibitor, inhibited FcR-mediated
phagocytosis in the presence of Cbl-70Z. These studies demonstrate that
mutants of Cbl can modulate the phagocytic pathway mediated by FcR
and imply a functional involvement of c-Cbl in Fc receptor-mediated
phagocytosis.
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