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Communicating
with the Cell Interior
We are interested in how cell surface receptors communicate with the interior
of the cell and how those communications regulate cellular behavior. In
particular, we are studying the mechanism of signaling by a class of related
receptors used by the immune system to detect and destroy invading microorganisms.
Clustering of these receptors, which include the B lymphocyte and T lymphocyte
antigen receptors and the Fc receptors of phagocytic cells, by the appropriate
antigen or antibody-antigen complex, leads to phosphorylation of key sequences
within the cytoplasmic domains of the receptors by Src-family tyrosine
kinases. This triggers the recruitment to the receptor and activation
of a second type of tyrosine kinase, Syk in B cells and phagocytic cells
or ZAP-70 in T cells. We have been using a genetic approach to dissect
the roles of Syk and the different Src-family kinases expressed in B cells
and phagocytic cells. Phagocytosis of antibody-coated particles by macrophages
(a method of destroying infectious agents) is completely dependent upon
Syk. In the absence of Syk, the macrophage begins to engulf the receptor-bound
particle and polymerizes actin under the membrane adjacent to the particle
normally, but cannot finish the job. In contrast, removal of all 3 Src-family
kinases expressed in these cells leads to a decrease in the rate of phagocytosis,
but with only a modest decrease in the amount of internalization. Syk
activation still occurs, although at a much reduced level. Thus, the role
of the Src-family kinases in phagocytosis may be primarily to recruit
and activate Syk, whereas Syk appears to be able to direct the final engulfment
of the particle. In the future, we'd like to understand how Syk can direct
the cytoskeletal and membrane events in this process. Also it is unclear
how the early events of phagocytosis are directed by the receptor.
Most cell types express several Src-family kinases, so one current question
is whether these Src-family members have redundant roles or unique roles
in signaling. B cells from mice in which the gene for Lyn (a Src-family
kinase) has been ablated, showed a delay in receptor phosphorylation and
Syk activation, as expected, but surprisingly showed enhanced biological
responses such as proliferation. We have found that Lyn is critical for
inhibitory signaling events that set the amplification level of signaling.
This function of Lyn appears to be largely unique, whereas the contribution
of Lyn to initiating signaling by the B cell antigen receptor appears
to shared by other Src-family kinases, with the net result that Lyn-deficient
B cells are hyperresponsive. Young animals lacking Lyn are normal, but
as they age they secrete autoantibodies and begin to suffer symptoms of
autoimmune disease. We are currently studying the causes of this autoimmunity,
since how human autoimmune diseases occur is still mysterious.
Selected Publications:
Crowley, M.T., P.S. Costello, M. Turner, F. Meng, C. Lowell, V.L.J. Tybulewicz,
and A.L. DeFranco (1997). A critical role for Syk in signal transduction
and phagocytosis mediated by Fcg receptors on macrophages. J. Exp. Med.
186, 1027.
Chan, V.W.F., C.A.Lowell, and A.L. DeFranco (1998). Defective negative
regulation of antigen receptor signaling in Lyn-deficient B lymphocytes.
Curr. Biol. 8, 545.
DeFranco, A.L. (1997). The complexity of signaling pathways activated
by the BCR. Curr. Opin. Immunl. 9, 296.
Contact Information:
Eamil:defranco@cgl.ucsf.edu
Phone: 415/ 476-5488
Address: Box 0552, Room HSW 1522
The University of California, San Francisco, CA 94143, (415) 476-9000
Copyright 2003, The Regents of the University of California.
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