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Surface Immunoglobulin-mediated Signal Transduction Involves Rapid Phosphorylation and Activation of the Protooncogene Product Raf-1 in Human B-Cells¹

Second Department of Medicine, Osaka University Medical School, 1-1-50, Fukushima-ku, Osaka 553, Japan [T. T., Y. K., A. K., H. I., H. Y., I. M., Y. K., T. Y.], and Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115 [B. D., J. D. G.]

The protooncogene product, Raf-1, is a serine/threonine kinase and has been implicated as an intermediate in signal transduction mechanisms. We examined neoplastic and normal B cells for phosphorylation and activation of Raf-1 protein in response to anti-immunoglobulin antibody (anti-Ig). Anti-Ig induced rapid phosphorylation of Raf-1 protein in both neoplastic B-cells of hairy cell leukemia and normal tonsillar B-cells which proliferated well in response to anti-Ig. The increase in phosphorylation was due primarily to an increase in phosphoserine. The immune complex kinase assay using Histone V-S as an exogenous substrate also showed an increase in Raf-1-associated kinase activity. An inhibitor of protein kinase C, H7, inhibited the proliferation as well as the Raf-1 phosphorylation in response to the proliferative signal of anti-Ig. Further, downregulation of protein kinase C by the treatment with 12-phorbol 13-myristic acid significantly abrogated the induction of Raf-1 phosphorylation. These results suggest that, in human B-cells, Raf-1 protein may be involved in the signal transduction pathway mediated by surface immunoglobulin, and that it may be, at least partially, phosphorylated by activated PKC.

¹ This work was supported in part by grants from the Ministry of Education, Science, and Culture and by the Osaka Cancer Research Foundation (Y. K.).

² To whom requests for reprints should be addressed, at The Second Department of Internal Medicine, Osaka University Medical School, 1-1-50, Fukushima, Fukushima-ku, Osaka 553, Japan.

Received 2/ 8/91. Accepted 11/13/91.

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