Editors' ChoiceImmunology

Knock-outs Show Cbl Function in T cells

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Science's STKE  18 Jan 2000:
Vol. 2000, Issue 15, pp. tw3
DOI: 10.1126/stke.2000.15.tw3

The Cbl proteins are adaptors that interact with multiple signaling proteins and function to regulate signaling through antigen and growth factor receptors. They appear to act, at least in part, by inhibiting signaling through tyrosine kinases. Bachmaier et al. and Chiang et al. attempt to clarify the physiological role of Cbl-b in T cells by analyzing mice in which the cbl-b gene was deleted. T cells from the Cbl-b-/- animals showed decreased requirement for costimulation through CD28 when stimulated though the T cell antigen receptor (TCR). In fact, Chiang et al. show that the cbl-b-/- mutation restored IL-2 production in response to TCR stimulation in T cells from CD28-/- mice and restored a normal T cell anitbody response in vivo in Cbl-b-/- CD28-/- mice. Lack of Cbl-b was associated with increased activation of the guanine nucleotide exchange factor Vav, but not changes in tyrosine kinase activity or other TCR signaling events. The authors note that defects in Cbl signaling could contribute to autoimmune diseases. Elsewhere, evidence continues to accumulate from cell lines for an effect of Cbl to limit tyrosine kinase activity. Andoniou et al. provide evidence that Cbl promotes degradation of the tyrosine kinase Fyn.

Bachmaier, K., Krawczyk, C., Kozieradzki, I., Kong, Y.-Y., Sasaki, T., Oliveira-dos-Santos, A., Mariathasan, S., Bouchard, D., Wakeham, A., Itie, A., Le, J., Ohashi, P.S., Sarosi, I., Nishina, H., Lipkowitz, S., and Penninger, J.M. (2000) Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b. Nature 403: 211-216. [Online Journal]

Chiang, Y.J., Kole, H.K., Brown, K., Naramura, M., Fukuhara, S., Hu, R.J., Jang, I.K., Gutkind, J.S., Shevach, E., and Gu, H. (2000) Cbl-b regulates the CD28 dependence of T-cell activation. Nature 403: 216-220. [Online Journal]

Andoniou, C.E., Lill, N.L., Thien, C.B., Lupher, M.L. Jr., Ota, S., Bowtell, D.D., Scaife, R.M., Langdon W.Y., Band, H. (2000) The Cbl proto-oncogene product negatively regulates the Src-family tyrosine kinase Fyn by enhancing its degradation. Mol. Cell. Biol. 20: 851-867. [Abstract] [Full Text]

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